TY  - JOUR
AB  - BACKGROUND: The renal epithelial sodium channel (ENaC) is essential for sodium balance and blood pressure control. ENaC undergoes complex proteolytic activation by not yet clearly identified tubular proteases. Here, we examined a potential role of transmembrane serine protease 2 (TMPRSS2). METHODS: Murine ENaC and TMPRSS2 were (co-)expressed in Xenopus laevis oocytes. ENaC cleavage and function were studied in TMPRSS2-deficient murine cortical collecting duct (mCCDcl1) cells and TMPRSS2-knockout (Tmprss2-/-) mice. Short-circuit currents (ISC) were measured to assess ENaC-mediated transepithelial sodium transport of mCCDcl1 cells. The mCCDcl1 cell transcriptome was studied using RNA sequencing. The effect of low-sodium diet with or without high potassium were compared in Tmprss2-/- and wildtype mice using metabolic cages. ENaC-mediated whole-cell currents were recorded from microdissected tubules of Tmprss2-/- and wildtype mice. RESULTS: In oocytes, co-expression of murine TMPRSS2 and ENaC resulted in fully cleaved γ-ENaC and ∼2-fold stimulation of ENaC currents. High baseline expression of TMPRSS2 was detected in mCCDcl1 cells without a stimulatory effect of aldosterone on its function or transcription. TMPRSS2 knockout in mCCDcl1 cells compromised γ-ENaC cleavage and reduced baseline and aldosterone-stimulated ISC which could be rescued by chymotrypsin. A compensatory transcriptional upregulation of other proteases was not observed. Tmprss2-/- mice kept on standard diet exhibited no apparent phenotype, but renal γ-ENaC cleavage was altered. In response to a low-salt diet, particularly with high potassium intake, Tmprss2-/- mice increased plasma aldosterone significantly more than wildtype mice to achieve a similar reduction of renal sodium excretion. Importantly, the stimulatory effect of trypsin on renal tubular ENaC currents was much more pronounced in Tmprss2-/- mice than that in wildtype mice. This indicated the presence of incompletely cleaved and less active channels at the cell surface of TMPRSS2-deficient tubular epithelial cells. CONCLUSIONS: TMPRSS2 contributes to proteolytic ENaC activation in mouse kidney in vivo.
AU  - Sure, F.*
AU  - Afonso, S.*
AU  - Essigke, D.
AU  - Schmidt, P.*
AU  - Kalo, M.Z.*
AU  - Nesterov, V.*
AU  - Kißler, A.*
AU  - Bertog, M.*
AU  - Rinke, R.*
AU  - Wittmann, S.*
AU  - Broeker, K.A.E.*
AU  - Gramberg, T.*
AU  - Artunc, F.
AU  - Korbmacher, C.*
AU  - Ilyaskin, A.V.*
C1  - 72125
C2  - 56525
CY  - 1401 H Street Nw, Suite 900, Washington, Dc 20005, United States
TI  - Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney.
JO  - J. Am. Soc. Nephrol.
PB  - Amer Soc Nephrology
PY  - 2024
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . RESULTS: Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
AU  - Matias-Garcia, P.R.
AU  - Wilson, R.
AU  - Guo, Q.*
AU  - Zaghlool, S.*
AU  - Eales, J.*
AU  - Xu, X.*
AU  - Charchar, F.J.*
AU  - Dormer, J.*
AU  - Maalmi, H.*
AU  - Schlosser, P.*
AU  - Elhadad, M.A.
AU  - Nano, J.
AU  - Sharma, S.
AU  - Peters, A.
AU  - Fornoni, A.*
AU  - Mook-Kanamori, D.*
AU  - Winkelmann, J.
AU  - Danesh, J.*
AU  - di Angelantonio, E.*
AU  - Ouwehand, W.*
AU  - Watkins, N.*
AU  - Roberts, D.*
AU  - Petrera, A.
AU  - Graumann, J.*
AU  - Koenig, W.*
AU  - Hveem, K.*
AU  - Jonasson, C.*
AU  - Köttgen, A.*
AU  - Butterworth, A.*
AU  - Prunotto, M.*
AU  - Hauck, S.M.
AU  - Herder, C.*
AU  - Suhre, K.*
AU  - Gieger, C.
AU  - Tomaszewski, M.*
AU  - Teumer, A.*
AU  - Waldenberger, M.
C1  - 62336
C2  - 50708
CY  - 1725 I St, Nw Ste 510, Washington, Dc 20006 Usa
SP  - 1747-1763
TI  - Plasma proteomics of renal function: A trans-ethnic metaanalysis and Mendelian randomization study.
JO  - J. Am. Soc. Nephrol.
VL  - 32
IS  - 7
PB  - Amer Soc Nephrology
PY  - 2021
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Background: Maladaptive ER stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell death-promoting transcription factor C/EBP homologous protein (CHOP). We determined whether therapy with locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorates experimental DKD. Methods: Following an in vivo dose-escalation study, we determined the efficacy of CHOPASO in the early and later stages of experimental DKD (8- or 16-week-old db/db mice, respectively) alone or in combination with an angiotensin-converting enzyme inhibitor (ACEi). Renal functional parameters and morphological analyses were used to determine the effects. Renal gene expression profiling was conducted to determine differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. Results: CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. A significantly larger number of genes and disease pathways were affected by CHOP-ASO, including reduced Slc5a2 (sodium-glucose transport protein 2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented cell death of human kidney cells in vitro Conclusions: The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi in particular at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.
AU  - Shahzad, K.*
AU  - Fatima, S.*
AU  - Al-Dabet, M.M.*
AU  - Gadi, I.*
AU  - Khawaja, H.*
AU  - Ambreen, S.*
AU  - Elwakiel, A.*
AU  - Klöting, N.
AU  - Blüher, M.
AU  - Nawroth, P.*
AU  - Mertens, P.*
AU  - Michel, S.*
AU  - Jaschinski, F.*
AU  - Klar, R.*
AU  - Isermann, B.*
C1  - 62956
C2  - 51205
CY  - 1725 I St, Nw Ste 510, Washington, Dc 20006 Usa
SP  - 3066-3079
TI  - CHOP-ASO ameliorates glomerular and tubular damage on top of ACE inhibition in diabetic kidney disease.
JO  - J. Am. Soc. Nephrol.
VL  - 32
IS  - 12
PB  - Amer Soc Nephrology
PY  - 2021
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10(-6) Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10(-5)), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10(-10) Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10(-12)). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10(-8)). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.
AU  - Böger, C.A.*
AU  - Gorski, M.*
AU  - McMahon, G.M.*
AU  - Xu, H.*
AU  - Chang, Y.C.*
AU  - van der Most, P.J.*
AU  - Navis, G.*
AU  - Nolte, I.M.*
AU  - de Borst, M.H.*
AU  - Zhang, W.*
AU  - Lehne, B.*
AU  - Loh, M.*
AU  - Tan, S.T.*
AU  - Boerwinkle, E.*
AU  - Grams, M.E.*
AU  - Sekula, P.*
AU  - Li, M.*
AU  - Wilmot, B.*
AU  - Moon, J.G.*
AU  - Scheet, P.*
AU  - Cucca, F.*
AU  - Xiao, X.*
AU  - Lyytikäinen, L.-P.*
AU  - Delgado, G.*
AU  - Grammer, T.B.*
AU  - Kleber, M.E.*
AU  - Sedaghat, S.*
AU  - Rivadeneira, F.*
AU  - Corre, T.*
AU  - Kutalik, Z.*
AU  - Bergmann, S.*
AU  - Nielson, C.M.*
AU  - Srikanth, P.*
AU  - Teumer, A.*
AU  - Müller-Nurasyid, M.
AU  - Brockhaus, A.C.*
AU  - Pfeufer, A.*
AU  - Rathmann, W.*
AU  - Peters, A.
AU  - Matsumoto, M.*
AU  - de Andrade, M.*
AU  - Atkinson, E.J.*
AU  - Robinson-Cohen, C.*
AU  - de Boer, I.H.*
AU  - Hwang, S.J.*
AU  - Heid, I.M.*
AU  - Gögele, M.*
AU  - Concas, M.P.*
AU  - Tanaka, T.*
AU  - Bandinelli, S.*
AU  - Nalls, M.A.*
AU  - Singleton, A.*
AU  - Tajuddin, S.M.*
AU  - Adeyemo, A.*
AU  - Zhou, J.*
AU  - Doumatey, A.*
AU  - McWeeney, S.K.*
AU  - Murabito, J.*
AU  - Franceschini, N.*
AU  - Flessner, M.*
AU  - Shlipak, M.G.*
AU  - Wilson, J.G.*
AU  - Chen, G.*
AU  - Rotimi, C.N.*
AU  - Zonderman, A.B.*
AU  - Evans, M.K.*
AU  - Ferrucci, L.*
AU  - Devuyst, O.*
AU  - Pirastu, M.*
AU  - Shuldiner, A.*
AU  - Hicks, A.A.*
AU  - Pramstaller, P.P.*
AU  - Kestenbaum, B.*
AU  - Kardia, S.L.R.*
AU  - Turner, S.T.*
AU  - Study, L.C.*
AU  - Briske, T.E.*
AU  - Gieger, C.
AU  - Strauch, K.
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Völker, U.*
AU  - Nauck, M.*
AU  - Völzke, H.*
AU  - Vollenweider, P.*
AU  - Bochud, M.*
AU  - Waeber, G.*
AU  - Kähönen, M.*
AU  - Lehtimäki, T.*
AU  - März, W.*
AU  - Dehghan, A.*
AU  - Franco, O.H.*
AU  - Uitterlinden, A.G.*
AU  - Hofman, A.*
AU  - Taylor, H.A.*
AU  - Chambers, J.C.*
AU  - Kooner, J.S.*
AU  - Fox, C.S.*
AU  - Hitzemann, R.*
AU  - Orwoll, E.S.*
AU  - Pattaro, C.*
AU  - Schlessinger, D.*
AU  - Köttgen, A.*
AU  - Snieder, H.*
AU  - Parsa, A.*
AU  - Cohen, D.M.*
C1  - 51967
C2  - 43545
SP  - 2311-2321
TI  - NFAT5 and SLC4A10 loci associate with plasma osmolality.
JO  - J. Am. Soc. Nephrol.
VL  - 28
IS  - 8
PY  - 2017
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (n(stage1);111,666;n(stage2): 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; P-stage1<3.7 x10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4x 10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
AU  - Li, M.*
AU  - Li, Y.*
AU  - Weeks, O.*
AU  - Mijatovic, V.*
AU  - Teumer, A.*
AU  - Huffman, J.E.*
AU  - Tromp, G.*
AU  - Fuchsberger, C.*
AU  - Gorski, M.*
AU  - Lyytikäinen, L.-P.*
AU  - Nutile, T.*
AU  - Sedaghat, S.*
AU  - Sorice, R.*
AU  - Tin, A.*
AU  - Yang, Q.*
AU  - Ahluwalia, T.S.*
AU  - Arking, D.E.*
AU  - Bihlmeyer, N.A.*
AU  - Boeger, C.A.*
AU  - Carroll, R.J.*
AU  - Chasman, D.I.*
AU  - Comelis, M.C.*
AU  - Dehghan, A.*
AU  - Faul, J.D.*
AU  - Feitosa, M.F.*
AU  - Gambaro, G.*
AU  - Gasparini, P.*
AU  - Giulianini, F.*
AU  - Heid, I.M.
AU  - Huang, J.*
AU  - Imboden, M.*
AU  - Jackson, A.U.*
AU  - Jeff, J.*
AU  - Jhun, M.A.*
AU  - Katz, R.*
AU  - Kifley, A.*
AU  - Kilpeläinen, T.O.*
AU  - Kumar, A.*
AU  - Laakso, M.*
AU  - Li-Gao, R.*
AU  - Lohman, K.*
AU  - Lu, Y.*
AU  - Maegi, R.*
AU  - Malerba, G.*
AU  - Mihailov, E.*
AU  - Mohlke, K.L.*
AU  - Mook-Kanamori, D.O.*
AU  - Robino, A.*
AU  - Ruderfer, D.*
AU  - Salvi, E.*
AU  - Schick, U.M.*
AU  - Schulz, C.*
AU  - Smith, A.V.*
AU  - Smith, J.A.*
AU  - Traglia, M.*
AU  - Yerges-Armstrong, L.M.*
AU  - Zhao, W.*
AU  - Goodarzi, M.O.*
AU  - Kraja, A.T.*
AU  - Liu, C.*
AU  - Wessel, J.*
AU  - Boerwinkle, E.*
AU  - Borecki, I.B.*
AU  - Bork-Jensen, J.*
AU  - Bottinger, E.P.*
AU  - Braga, D.*
AU  - Brandslund, I.*
AU  - Brody, J.A.*
AU  - Campbell, A.*
AU  - Carey, D.J.*
AU  - Christensen, C.*
AU  - Coresh, J.*
AU  - Crook, E.D.*
AU  - Curhan, G.C.*
AU  - Cusi, D.*
AU  - de Boer, I.H.*
AU  - de Vries, A.P.J.*
AU  - Denny, J.C.*
AU  - Devuyst, O.*
AU  - Dreisbach, A.W.*
AU  - Endlich, K.*
AU  - Esko, T.*
AU  - Franco, O.H.*
AU  - Fulop, T.*
AU  - Gerhard, G.S.*
AU  - Gluemer, C.*
AU  - Gottesman, O.*
AU  - Grarup, N.*
AU  - Gudnason, V.*
AU  - Hansen, T.*
AU  - Harris, T.B.*
AU  - Hayward, C.*
AU  - Hocking, L.J.*
AU  - Hofman, A.*
AU  - Hu, F.B.*
AU  - Husemoen, L.L.N.*
AU  - Jackson, R.D.*
AU  - Jorgensen, T.*
AU  - Jorgensen, M.E.*
AU  - Kaehoenen, M.*
AU  - Kardia, S.L.R.*
AU  - Koenig, W.*
AU  - Kooperberg, C.*
AU  - Kriebel, J.
AU  - Launer, L.J.*
AU  - Lauritzen, T.*
AU  - Lehtimäki, T.*
AU  - Levy, D.*
AU  - Linksted, P.*
AU  - Linneberg, A.*
AU  - Liu, Y.*
AU  - Loos, R.J.F.*
AU  - Lupo, A.*
AU  - Meisinger, C.
AU  - Melander, O.*
AU  - Metspalu, A.*
AU  - Mitchell, P.*
AU  - Nauck, M.*
AU  - Nuernberg, P.*
AU  - Orho-Melander, M.*
AU  - Parsa, A.*
AU  - Pedersen, O.*
AU  - Peters, A.
AU  - Peters, U.*
AU  - Polasek, O.*
AU  - Porteous, D.J.*
AU  - Probst-Hensch, N.M.*
AU  - Psaty, B.M.*
AU  - Qi, L.*
AU  - Raitakari, O.T.*
AU  - Reiner, A.P.*
AU  - Rettig, R.*
AU  - Ridker, P.M.*
AU  - Rivadeneira, F.*
AU  - Rossouw, J.E.*
AU  - Schmidt, F.*
AU  - Siscovick, D.*
AU  - Soranzo, N.*
AU  - Strauch, K.
AU  - Toniolo, D.*
AU  - Turner, S.T.*
AU  - Uitterlinden, A.G.*
AU  - Ulivi, S.*
AU  - Velayutham, D.*
AU  - Voelker, U.*
AU  - Völzke, H.*
AU  - Waldenberger, M.
AU  - Wang, J.J.*
AU  - Weir, D.R.*
AU  - Witte, D.R.*
AU  - Kuivaniemi, H.*
AU  - Fox, C.S.*
AU  - Franceschini, N.*
AU  - Goessling, W.*
AU  - Koettgen, A.*
AU  - Chu, A.Y.*
C1  - 50808
C2  - 42561
CY  - Washington
SP  - 981-994
TI  - SOS2 and ACP1 loci identified through large-scale exome chip analysis regulate kidney development and function.
JO  - J. Am. Soc. Nephrol.
VL  - 28
IS  - 3
PB  - Amer Soc Nephrology
PY  - 2017
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Established therapies for diabetic nephropathy (dNP) delay but do not prevent its progression. The shortage of established therapiesmay reflect the inability to target the tubular compartment. The chemical chaperone tauroursodeoxycholic acid (TUDCA) ameliorates maladaptive endoplasmic reticulum (ER) stress signaling and experimental dNP. Additionally, TUDCA activates the farnesoid X receptor (FXR), which is highly expressed in tubular cells.We hypothesized that TUDCA ameliorates maladaptive ER signaling via FXR agonism specifically in tubular cells. Indeed, TUDCA induced expression of FXR-dependent genes (SOCS3 and DDAH1) in tubular cells but not in other renal cells. In vivo, TUDCA reduced glomerular and tubular injury in db/db and diabetic endothelial nitric oxide synthase-deficient mice. FXR inhibition with Z-guggulsterone or vivo-morpholino targeting of FXR diminished the ER-stabilizing and renoprotective effects of TUDCA. Notably, these in vivo approaches abolished tubular but not glomerular protection by TUDCA. Combined intervention with TUDCA and the angiotensin-converting enzyme inhibitor enalapril in 16-week-old db/db mice reduced albuminuria more efficiently than did either treatment alone. Although both therapies reduced glomerular damage, only TUDCA ameliorated tubular damage. Thus, interventions that specifically protect the tubular compartment in dNP, such as FXR agonism, may provide renoprotective effects on top of those achieved by inhibiting angiotensin-converting enzyme.
AU  - Marquardt, A.*
AU  - Al-Dabet, M.M.*
AU  - Ghosh, S.*
AU  - Kohli, S.*
AU  - Manoharan, J.*
AU  - Elwakiel, A.*
AU  - Gadi, I.*
AU  - Bock, F.*
AU  - Nazir, S.*
AU  - Wang, H.*
AU  - Lindquist, J.A.*
AU  - Nawroth, P.P.
AU  - Madhusudhan, T.*
AU  - Mertens, P.R.*
AU  - Shahzad, K.*
AU  - Isermann, B.*
C1  - 52282
C2  - 43870
CY  - Washington
SP  - 3182-3189
TI  - Farnesoid X receptor agonism protects against diabetic tubulopathy: Potential add-on therapy for diabetic nephropathy.
JO  - J. Am. Soc. Nephrol.
VL  - 28
IS  - 11
PB  - Amer Soc Nephrology
PY  - 2017
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Glycans constitute the most abundant and diverse form of the post-translational modifications, and animal studies have suggested the involvement of IgG glycosylation in mechanisms of renal damage. Here, we explored the associations between IgG glycans and renal function in 3274 individuals from the TwinsUK registry. We analyzed the correlation between renal function measured as eGFR and 76 N-glycan traits using linear regressions adjusted for covariates and multiple testing in the larger population. We replicated our results in 31 monozygotic twin pairs discordant for renal function. Results from both analyses were then meta-analyzed. Fourteen glycan traits were associated with renal function in the discovery sample (P<6.5×10(-4)) and remained significant after validation. Those glycan traits belong to three main glycosylation features: galactosylation, sialylation, and level of bisecting N-acetylglucosamine of the IgG glycans. These results show the role of IgG glycosylation in kidney function and provide novel insight into the pathophysiology of CKD and potential diagnostic and therapeutic targets.
AU  - Barrios, C.*
AU  - Zierer, J.
AU  - Gudelj, I.*
AU  - Stambuk, J.*
AU  - Ugrina, I.*
AU  - Rodriguez, E.*
AU  - Soler, M.J.*
AU  - Pavić, T.*
AU  - Simurina, M.*
AU  - Keser, T.*
AU  - Pučić-Baković, M.*
AU  - Mangino, M.*
AU  - Pascual, J.*
AU  - Spector, T.D.*
AU  - Lauc, G.*
AU  - Menni, C.*
C1  - 46373
C2  - 37560
CY  - Washington
SP  - 933-941
TI  - Glycosylation profile of IgG in moderate kidney dysfunction.
JO  - J. Am. Soc. Nephrol.
VL  - 27
IS  - 3
PB  - Amer Soc Nephrology
PY  - 2016
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Heme oxygenase-1 (HO-1) catalyzes the degradation of heme, which may be involved in the pathogenesis of AKI. Length polymorphisms in the number of GT dinucleotide repeats in the HO-1 gene (HMOX1) promoter inversely associate with HMOX1 mRNA expression. We analyzed the association between allelic frequencies of GT repeats in the HMOX1 gene promoter and postoperative AKI in 2377 white patients who underwent cardiac surgery with cardiopulmonary bypass. We categorized patients as having the short allele (S; <27 GT repeats) or long allele (L; ≥27 GT repeats), and defined AKI as an increase in serum creatinine ≥0.3 mg/dl within 48 hours or ≥50% within 5 days, or the need for RRT. Compared with patients with the SS genotype, patients with the LL genotype had 1.58-fold (95% confidence interval, 1.06 to 2.34; P=0.02) higher odds of AKI. After adjusting for baseline and operative characteristics, the odds ratio for AKI per L allele was 1.26 (95% confidence interval, 1.05 to 1.50; P=0.01). In conclusion, longer GT repeats in the HMOX1 gene promoter associate with increased risk of AKI after cardiac surgery, consistent with heme toxicity as a pathogenic feature of cardiac surgery-associated AKI, and with HO-1 as a potential therapeutic target.
AU  - Leaf, D.E.*
AU  - Body, S.C.*
AU  - Muehlschlegel, J.D.*
AU  - McMahon, G.M.*
AU  - Lichtner, P.
AU  - Collard, C.D.*
AU  - Shernan, S.K.*
AU  - Fox, A.A.*
AU  - Waikar, S.S.*
C1  - 48736
C2  - 41288
CY  - Washington
SP  - 3291-3297
TI  - Length polymorphisms in heme oxygenase-1 and AKI after cardiac surgery.
JO  - J. Am. Soc. Nephrol.
VL  - 27
IS  - 11
PB  - Amer Soc Nephrology
PY  - 2016
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria.
AU  - Mulay, S.R.*
AU  - Eberhard, J.N.*
AU  - Desai, J.*
AU  - Marschner, J.A.*
AU  - Kumar, S.V.*
AU  - Weidenbusch, M.*
AU  - Grigorescu, M.*
AU  - Lech, M.*
AU  - Eltrich, N.*
AU  - Müller, L.*
AU  - Hans, W.
AU  - Hrabě de Angelis, M.
AU  - Vielhauer, V.*
AU  - Hoppe, B.*
AU  - Asplin, J.*
AU  - Burzlaff, N.*
AU  - Hermann, M.*
AU  - Evan, A.*
AU  - Anders, H.J.*
C1  - 49458
C2  - 41818
CY  - Washington
SP  - 761-768
TI  - Hyperoxaluria requires TNF receptors to initiate crystal adhesion and kidney stone disease.
JO  - J. Am. Soc. Nephrol.
VL  - 28
IS  - 3
PB  - Amer Soc Nephrology
PY  - 2016
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Small molecules are extensively metabolized and cleared by the kidney. Changes in serum metabolite concentrations may result from impaired kidney function and can be used to estimate filtration (e.g., the established marker creatinine) or may precede and potentially contribute to CKD development. Here, we applied a nontargeted metabolomics approach using gas and liquid chromatography coupled to mass spectrometry to quantify 493 small molecules in human serum. The associations of these molecules with GFR estimated on the basis of creatinine (eGFRcr) and cystatin C levels were assessed in ≤1735 participants in the KORA F4 study, followed by replication in 1164 individuals in the TwinsUK registry. After correction for multiple testing, 54 replicated metabolites significantly associated with eGFRcr, and six of these showed pairwise correlation (r≥0.50) with established kidney function measures: C-mannosyltryptophan, pseudouridine, N-acetylalanine, erythronate, myo-inositol, and N-acetylcarnosine. Higher C-mannosyltryptophan, pseudouridine, and O-sulfo-L-tyrosine concentrations associated with incident CKD (eGFRcr
AU  - Sekula, P.*
AU  - Goek, O.N.*
AU  - Quaye, L.*
AU  - Barrios, C.*
AU  - Levey, A.S.*
AU  - Römisch-Margl, W.
AU  - Menni, C.*
AU  - Yet, I.*
AU  - Gieger, C.
AU  - Inker, L.A.*
AU  - Adamski, J.
AU  - Gronwald, W.*
AU  - Illig, T.
AU  - Dettmer, K.*
AU  - Krumsiek, J.
AU  - Oefner, P.J.*
AU  - Valdes, A.M.*
AU  - Meisinger, C.
AU  - Coresh, J.*
AU  - Spector, T.D.*
AU  - Mohney, R.P.*
AU  - Suhre, K.
AU  - Kastenmüller, G.
AU  - Köttgen, A.*
C1  - 46959
C2  - 39088
CY  - Washington
SP  - 1175-1188
TI  - A metabolome-wide association study of kidney function and disease in the general population.
JO  - J. Am. Soc. Nephrol.
VL  - 27
IS  - 4
PB  - Amer Soc Nephrology
PY  - 2016
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3ε mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy.
AU  - Suhre, K.
AU  - Schwartz, J.E.*
AU  - Sharma, V.K.*
AU  - Chen, Q.*
AU  - Lee, J.R.*
AU  - Muthukumar, T.*
AU  - Dadhania, D.M.*
AU  - Ding, R.*
AU  - Ikle, D.N.*
AU  - Bridges, N.D.*
AU  - Williams, N.M.*
AU  - Kastenmüller, G.
AU  - Karoly, E.D.*
AU  - Mohney, R.P.*
AU  - Abecassis, M.*
AU  - Friedewald, J.*
AU  - Knechtle, S.J.*
AU  - Becker, Y.T.*
AU  - Samstein, B.*
AU  - Shaked, A.*
AU  - Gross, S.S.*
AU  - Suthanthiran, M.*
C1  - 45119
C2  - 37208
CY  - Washington
SP  - 626-636
TI  - Urine metabolite profiles predictive of human kidney allograft status.
JO  - J. Am. Soc. Nephrol.
VL  - 27
IS  - 2
PB  - Amer Soc Nephrology
PY  - 2015
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Mutations of the LMX1B gene cause nail-patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes.
AU  - Burghardt, T.*
AU  - Kastner, J.*
AU  - Suleiman, H.*
AU  - Rivera-Milla, E.*
AU  - Stepanova, N.*
AU  - Lottaz, C.*
AU  - Kubitza, M.*
AU  - Böger, C.A.*
AU  - Schmidt, S.*
AU  - Gorski, M.*
AU  - de Vries, U.*
AU  - Schmidt, H.*
AU  - Hertting, I.*
AU  - Kopp, J.*
AU  - Rascle, A.*
AU  - Moser, M.*
AU  - Heid, I.M.
AU  - Warth, R.*
AU  - Spang, R.*
AU  - Wegener, J.
AU  - Mierke, C.T.*
AU  - Englert, C.*
AU  - Witzgall, R.*
C1  - 28287
C2  - 33063
SP  - 1830-1848
TI  - LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys.
JO  - J. Am. Soc. Nephrol.
VL  - 24
IS  - 11
PB  - Amer. Soc. Nephrology
PY  - 2013
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
AU  - Parsa, A.*
AU  - Fuchsberger, C.*
AU  - Köttgen, A.*
AU  - O'Seaghdha, C.M.*
AU  - Pattaro, C.*
AU  - de Andrade, M.*
AU  - Chasman, D.I.*
AU  - Teumer, A.*
AU  - Endlich, K.*
AU  - Olden, M.*
AU  - Chen, M.H.*
AU  - Tin, A.*
AU  - Kim, Y.J.*
AU  - Taliun, D.*
AU  - Li, M.*
AU  - Feitosa, M.*
AU  - Gorski, M.*
AU  - Yang, Q.*
AU  - Hundertmark, C.*
AU  - Foster, M.C.*
AU  - Glazer, N.*
AU  - Isaacs, A.*
AU  - Rao, M.*
AU  - Smith, A.V.*
AU  - O'Connell, J.R.*
AU  - Struchalin, M.*
AU  - Tanaka, T.*
AU  - Li, G.*
AU  - Hwang, S.J.*
AU  - Atkinson, E.J.*
AU  - Lohman, K.*
AU  - Cornelis, M.C.*
AU  - Johansson, A.*
AU  - Tönjes, A.*
AU  - Dehghan, A.*
AU  - Couraki, V.*
AU  - Holliday, E.G.*
AU  - Sorice, R.*
AU  - Kutalik, Z.*
AU  - Lehtimäki, T.*
AU  - Esko, T.*
AU  - Deshmukh, H.*
AU  - Ulivi, S.*
AU  - Chu, A.Y.*
AU  - Murgia, F.*
AU  - Trompet, S.*
AU  - Imboden, M.*
AU  - Kollerits, B.*
AU  - Pistis, G.*
AU  - Harris, T.B.*
AU  - Launer, L.J.*
AU  - Aspelund, T.*
AU  - Eiriksdottir, G.*
AU  - Mitchell, B.D.*
AU  - Boerwinkle, E.*
AU  - Schmidt, H.*
AU  - Hofer, E.*
AU  - Hu, F.*
AU  - Demirkan, A.*
AU  - Oostra, B.A.*
AU  - Turner, S.T.*
AU  - Ding, J.*
AU  - Andrews, J.S.*
AU  - Freedman, B.I.*
AU  - Giulianini, F.*
AU  - Koenig, W.*
AU  - Illig, T.
AU  - Döring, A.
AU  - Wichmann, H.-E.
AU  - Zgaga, L.*
AU  - Zemunik, T.*
AU  - Boban, M.*
AU  - Minelli, C.*
AU  - Wheeler, H.E.*
AU  - Igl, W.*
AU  - Zaboli, G.*
AU  - Wild, S.H.*
AU  - Wright, A.F.*
AU  - Campbell, H.*
AU  - Ellinghaus, D.*
AU  - Nöthlings, U.*
AU  - Jacobs, G.*
AU  - Biffar, R.*
AU  - Ernst, F.*
AU  - Homuth, G.*
AU  - Kroemer, H.K.*
AU  - Nauck, M.*
AU  - Stracke, S.*
AU  - Völker, U.*
AU  - Völzke, H.*
AU  - Kovacs, P.*
AU  - Stumvoll, M.*
AU  - Mägi, R.*
AU  - Hofman, A.*
AU  - Uitterlinden, A.G.*
AU  - Rivadeneira, F.*
AU  - Aulchenko, Y.S.*
AU  - Polasek, O.*
AU  - Hastie, N.*
AU  - Vitart, V.*
AU  - Helmer, C.*
AU  - Wang, J.J.*
AU  - Stengel, B.*
AU  - Ruggiero, D.*
AU  - Bergmann, S.*
AU  - Kähönen, M.*
AU  - Viikari, J.*
AU  - Nikopensius, T.*
AU  - Province, M.*
AU  - Colhoun, H.*
AU  - Doney, A.*
AU  - Robino, A.*
AU  - Krämer, B.K.*
AU  - Portas, L.*
AU  - Ford, I.*
AU  - Buckley, B.M.*
AU  - Adam, M.*
AU  - Thun, G.A.*
AU  - Paulweber, B.*
AU  - Haun, M.*
AU  - Sala, C.*
AU  - Mitchell, P.*
AU  - Ciullo, M.*
AU  - Vollenweider, P.*
AU  - Raitakari, O.*
AU  - Metspalu, A.*
AU  - Palmer, C.*
AU  - Gasparini, P.*
AU  - Pirastu, M.*
AU  - Jukema, J.W.*
AU  - Probst-Hensch, N.M.*
AU  - Kronenberg, F.*
AU  - Toniolo, D.*
AU  - Gudnason, V.*
AU  - Shuldiner, A.R.*
AU  - Coresh, J.*
AU  - Schmidt, R.*
AU  - Ferrucci, L.*
AU  - van Duijn, C.M.*
AU  - Borecki, I.*
AU  - Kardia, S.L.*
AU  - Liu, Y.*
AU  - Curhan, G.C.*
AU  - Rudan, I.*
AU  - Gyllensten, U.*
AU  - Wilson, J.F.*
AU  - Franke, A.*
AU  - Pramstaller, P.P.*
AU  - Rettig, R.*
AU  - Prokopenko, I.*
AU  - Witteman, J.*
AU  - Hayward, C.*
AU  - Ridker, P.M.*
AU  - Bochud, M.*
AU  - Heid, I.M.
AU  - Siscovick, D.S.*
AU  - Fox, C.S.*
AU  - Kao, W.L.*
AU  - Böger, C.A.*
C1  - 28741
C2  - 33536
SP  - 2105-2117
TI  - Common variants in mendelian kidney disease genes and their association with renal function.
JO  - J. Am. Soc. Nephrol.
VL  - 24
IS  - 12
PY  - 2013
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Uromodulin/Tamm-Horsfall protein is not immunostimulatory in the tubular lumen, but through unknown mechanisms it can activate dendritic cells and promote inflammation in the renal interstitium. Here, we noted that uromodulin isolated from human urine aggregates to large, irregular clumps with a crystal-like ultrastructure. These uromodulin nanoparticles activated isolated human monocytes to express costimulatory molecules and to secrete the mature proinflammatory cytokines, including IL-1 beta. Full release of IL-1 beta in response to uromodulin depended on priming of pro-IL-1 beta expression by Toll-like receptors, TNF-alpha, or IL-1 alpha. In addition, uromodulin-induced secretion of mature IL-1 beta depended on the NLRP3 inflammasome, its linker molecule ASC, and pro-IL-1 beta cleavage by caspase-1. Activation of NLRP3 required phagocytosis of uromodulin particles into lysosomes, cathepsin leakage, oxidative stress, and potassium efflux from the cell. Taken together, these data suggest that uromodulin is a NLRP3 agonist handled by antigen-presenting cells as an immunostimulatory nanoparticle. Thus, in the presence of tubular damage that exposes the renal interstitium, uromodulin becomes an endogenous danger signal. The inability of renal parenchymal cells to secrete IL-1 beta may explain why uromodulin remains immunologically inert inside the luminal compartment of the urinary tract.
AU  - Darisipudi, M.N.*
AU  - Thomasova, D.*
AU  - Mulay, S.R.*
AU  - Brech, D.
AU  - Nößner, E.
AU  - Liapis, H.*
AU  - Anders, H.J.*
C1  - 11106
C2  - 30538
SP  - 1783-1789
TI  - Uromodulin triggers IL-1β-dependent innate immunity via the NLRP3 inflammasome.
JO  - J. Am. Soc. Nephrol.
VL  - 23
IS  - 11
PB  - Amer. Soc. Nephrology
PY  - 2012
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes. Elevated levels of urinary albumin (albuminuria) are a cardinal manifestation of chronic kidney disease (CKD) and affect as many as 8% of adults from the United States and 6% of adults from Germany. Higher levels of albuminuria, even within the low normal range, are associated with not only increased risks of ESRD but also cardiovascular disease and mortality. Moreover, the presence of albuminuria offers key prognostic information at each stage of decline in GFR. However, the pathophysiologic basis of albuminuria remains incompletely understood, and as a result, interventions for the prevention and treatment of albuminuria are limited. Diabetes mellitus and hypertension are key risk factors for albuminuria, but neither of these factors fully account for the high prevalence of albuminuria nor its association with adverse health outcomes. Heritability of albuminuria ranges from 0.16 to 0.49 in families enriched with hypertension or diabetes. Rare genetic variants are known to cause monogenic diseases featuring severe, nephrotic range proteinuria. However, linkage or candidate gene studies have not reproducibly identified common genetic variants in association with lower levels of albuminuria. Given recent successes in the use of genome-wide association studies (GWAS) of quantitative traits that can lead to the identification of relevant variants for a disease phenotype, we conducted a genome-wide association (GWA) analysis of albuminuria in 31,580 participants of European ancestry from the CKDGen Consortium, with follow-up in 27,746 additional participants. Albuminuria was analyzed as the quantitative trait urinary albumin-to-creatinine ratio (UACR) and as the dichotomous trait microalbuminuria (MA). Concurrently, we performed an analysis of albuminuria in the CARe Consortium using the ITMAT/Broad/CARE Vascular Disease 50k (IBC) single-nucleotide polymorphism (SNP) chip array in 19,499 Europeans and 6981 African Americans. Here, we report the results of our combined findings.
AU  - Böger, C.A.*
AU  - Chen, M.H.*
AU  - Tin, A.*
AU  - Olden, M.*
AU  - Köttgen, A.*
AU  - de Boer, I.H.*
AU  - Fuchsberger, C.*
AU  - O'Seaghdha, C.M.*
AU  - Pattaro, C.*
AU  - Teumer, A.*
AU  - Liu, C.-T.*
AU  - Glazer, N.L.*
AU  - Li, M.*
AU  - O'Conne, J.R.*
AU  - Tanaka, T.*
AU  - Peralta, C.A.*
AU  - Kutalik, Z.*
AU  - Luan, J.*
AU  - Zhao, J.H.*
AU  - Hwang, S.J.*
AU  - Akylbekova, E.*
AU  - Kramer, H.*
AU  - van der Harst, P.*
AU  - Smith, A.V.*
AU  - Lohman, K.*
AU  - de Andrade, M.*
AU  - Hayward, C.*
AU  - Kollerits, B.*
AU  - Tönjes, A.*
AU  - Aspelund, T.*
AU  - Ingelsson, E.*
AU  - Eiriksdottir, G.*
AU  - Launer, L.J.*
AU  - Harris, T.B.*
AU  - Shuldiner, A.R.*
AU  - Mitchell, B.D.*
AU  - Arking, D.E.*
AU  - Franceschini, N.*
AU  - Boerwinkle, E.*
AU  - Egan, J.*
AU  - Hernandez, D.*
AU  - Reilly, M.*
AU  - Townsend, R.R.*
AU  - Lumley, T.*
AU  - Siscovick, D.S.*
AU  - Psaty, B.M.*
AU  - Kestenbaum, B.*
AU  - Haritunians, T.*
AU  - Bergmann, S.*
AU  - Vollenweider, P.*
AU  - Waeber, G.*
AU  - Mooser, V.*
AU  - Waterworth, D.*
AU  - Johnson, A.D.*
AU  - Florez, J.C*
AU  - Meigs, J.B.*
AU  - Lu, X.N.*
AU  - Turner, S.T.
AU  - Atkinson, E.J.*
AU  - Leak, T.S.*
AU  - Aasarod, K.*
AU  - Skorpen, F.*
AU  - Syvanen, A.C.*
AU  - Illig, T.
AU  - Baumert, J.J.
AU  - Koenig, W.*
AU  - Krämer, B.K.*
AU  - Devuyst, O.*
AU  - Mychaleckyj, J.C.*
AU  - Minelli, C.*
AU  - Bakker, S.J.L.*
AU  - Kedenko, L.*
AU  - Paulweber, B.*
AU  - Coassin, S.*
AU  - Endlich, K.*
AU  - Kroemer, H.K.*
AU  - Biffar, R.*
AU  - Stracke, S.*
AU  - Voelzke, H.*
AU  - Stumvoll, M.*
AU  - Mägi, R.*
AU  - Campbell, H.*
AU  - Vitart, V.*
AU  - Hastie, N.D.*
AU  - Gudnason, V.*
AU  - Kardia, S.L.R.*
AU  - Liu, Y.M.*
AU  - Polasek, O.*
AU  - Curhan, G.*
AU  - Kronenberg, F.*
AU  - Prokopenko, I.*
AU  - Rudan, I.*
AU  - Ärnlöv, J.*
AU  - Hallan, S.*
AU  - Navis, G.*
AU  - Parsa, A.*
AU  - Ferrucci, L.*
AU  - Coresh, J.*
AU  - Shlipak, M.G.*
AU  - Bul, S.B.*
AU  - Paterson, A.D.*
AU  - Wichmann, H.-E.
AU  - Wareham, N.J.*
AU  - Loos, R.J.F.*
AU  - Rotter, J.I.*
AU  - Pramstaller, P.P.*
AU  - Cupples, L.A.*
AU  - Beckmann, J.S.*
AU  - Yang, Q.O.*
AU  - Heid, I.M.
AU  - Rettig, R.*
AU  - Dreisbach, A.W.*
AU  - Bochud, M.*
AU  - Fox, C.S.*
AU  - Kao, W.H.L.*
C1  - 6285
C2  - 28350
SP  - 555-570
TI  - CUBN is a gene locus for albuminuria.
JO  - J. Am. Soc. Nephrol.
VL  - 22
IS  - 3
PB  - Amer Soc Nephrology
PY  - 2011
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
AU  - Kestenbaum, B.*
AU  - Glazer, N.L.*
AU  - Köttgen, A.*
AU  - Felix, J.F.*
AU  - Hwang, S.J.*
AU  - Liu, Y.M.*
AU  - Lohman, K.*
AU  - Kritchevsky, S.B.*
AU  - Hausman, D.B.*
AU  - Petersen, A.-K.
AU  - Gieger, C.
AU  - Ried, J.S.
AU  - Meitinger, T.
AU  - Strom, T.M.
AU  - Wichmann, H.-E.
AU  - Campbell, H.*
AU  - Hayward, C.*
AU  - Rudan, I.*
AU  - de Boer, I.H.*
AU  - Psaty, B.M.*
AU  - Rice, K.M.*
AU  - Chen, Y.D.I.*
AU  - Li, M.*
AU  - Arking, D.E.*
AU  - Boerwinkle, E.*
AU  - Coresh, J.*
AU  - Yang, Q.O.*
AU  - Levy, D.*
AU  - van Rooij, F.J.A.*
AU  - Dehghan, A.*
AU  - Rivadeneira, F.*
AU  - Uitterlinden, A.G.*
AU  - Hofman, A.*
AU  - van Duijn, C.M.*
AU  - Shlipak, M.G.*
AU  - Kao, W.H.L.*
AU  - Witteman, J.C.M.*
AU  - Siscovick, D.S.*
AU  - Fox, C.S.*
C1  - 5416
C2  - 27485
SP  - 1223-1232
TI  - Common genetic variants associate with serum phosphorus concentration.
JO  - J. Am. Soc. Nephrol.
VL  - 21
IS  - 7
PB  - American Society of Nephrology
PY  - 2010
SN  - 1046-6673
ER  - 

TY  - JOUR
AB  - MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8+ T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.
AU  - Pérez de Lema, G.*
AU  - Maier, H.*
AU  - Franz, T.J.
AU  - Escribese, M.*
AU  - Chilla, S.*
AU  - Segerer, S.*
AU  - Camarasa, N.*
AU  - Schmid, H.*
AU  - Banas, B.*
AU  - Kalaydjiev, S.
AU  - Busch, D.H.
AU  - Pfeffer, K.*
AU  - Mampaso, F.*
AU  - Schlöndorff, D.*
AU  - Luckow, B.*
C1  - 28372
C2  - 33338
SP  - 3592-3601
TI  - Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice.
JO  - J. Am. Soc. Nephrol.
VL  - 16
IS  - 12
PB  - Amer. Soc. Nephrology
PY  - 2005
SN  - 1046-6673
ER  - 

TY  - JOUR
AU  - Rantanen, M.*
AU  - Palmen, T.*
AU  - Pätäri, A.*
AU  - Ahola, H.*
AU  - Lehtonen, S.*
AU  - Äström, E.*
AU  - Floß, T.
AU  - Vauti, F.
AU  - Wurst, W.
AU  - Ruiz, P.*
AU  - Kerjaschki, D.*
AU  - Holthöfer, H.*
C1  - 10109
C2  - 20978
SP  - 1586-1594
TI  - Nephrin TRAP Mice Lack Slit Diaphragms and Show Fibrotic Glomeruli and Cystic Tubular Lesions.
JO  - J. Am. Soc. Nephrol.
VL  - 13
PY  - 2002
SN  - 1046-6673
ER  -