TY  - JOUR
AB  - The kidney controls systemic inorganic phosphate (Pi) levels by adapting reabsorption to Pi intake. Renal Pi reabsorption is mostly mediated by sodium-phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) which are tightly controlled by various hormones including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). PTH and FGF23 rise in response to Pi intake and decrease NaPi-IIa and NaPi-IIc brush border membrane abundance enhancing phosphaturia. Phosphaturia and transporter regulation occur even in the absence of PTH and FGF23 signalling. The calcium-sensing receptor (CaSR) regulates PTH and FGF23 secretion, and may also directly affect renal Pi handling. Here, we combined pharmacological and genetic approaches to examine the role of the CaSR in the acute phosphaturic response to Pi-loading. Animals pretreated with the calcimimetic cinacalcet were hyperphosphatemic, had blunted PTH levels upon Pi administration, a reduced Pi-induced phosphaturia and no Pi-induced NaPi-IIa downregulation. The calcilytic NPS-2143 exaggerated the PTH response to Pi-loading but did not abolish Pi-induced downregulation of NaPi-IIa. In mice with a dominant inactivating mutation in the Casr (CasrBCH002), baseline NaPi-IIa expression was higher, whereas downregulation of transporter expression was blunted in double CasrBCH002/PTH KO transgenic animals. Thus, in response to an acute Pi load, acute modulation of the CaSR affects the endocrine and renal response, while chronic genetic inactivation, displays only subtle differences in the downregulation of NaPi-IIa and NaPi-IIc renal expression. We did not find evidence that the CaSR impacts on the acute renal response to oral Pi-loading beyond its role in regulating PTH secretion.
AU  - Daryadel, A.*
AU  - Küng, C.J.*
AU  - Haykir, B.*
AU  - Sabrautzki, S.
AU  - Hrabě de Angelis, M.
AU  - Hernando, N.*
AU  - Rubio-Aliaga, I.*
AU  - Wagner, C.A.*
C1  - 70375
C2  - 55546
CY  - 6120 Executive Blvd, Suite 600, Rockville, Md, United States
SP  - F792-F801
TI  - The calcium-sensing receptor has only a parathyroid hormone-dependent role in the acute response of renal phosphatetransporters to phosphate intake.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 326
IS  - 5
PB  - Amer Physiological Soc
PY  - 2024
SN  - 1931-857X
ER  - 

TY  - JOUR
AB  - Proteolytic activation of the renal epithelial sodium channel ENaC involves cleavage events in its α- and γ-subunits and is thought to mediate sodium retention in nephrotic syndrome (NS). However, detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to reliably discriminate full-length α- and γ-ENaC and their cleavage products after proteolysis at their proximal and distal cleavage sites (designated from the N-terminus), respectively. Proteolytic ENaC activation was investigated in kidneys from mice with experimental NS induced by doxorubicin or inducible podocin deficiency with or without treatment with the serine protease inhibitor aprotinin. Nephrotic mice developed sodium retention and increased expression of fragments of α- and γ-ENaC cleaved at both the proximal and more prominently at the distal cleavage site, respectively. Treatment with aprotinin but not with the mineralocorticoid receptor antagonist canrenoate prevented sodium retention and upregulation of the cleavage products in nephrotic mice. Increased expression of cleavage products of α- and γ-ENaC was similarly found in healthy mice treated with a low salt diet, sensitive to mineralocorticoid receptor blockade. In human nephrectomy specimens, γ-ENaC was found in the full-length form and predominantly cleaved at its distal cleavage site. In conclusion, murine experimental NS leads to aprotinin-sensitive proteolytic activation of ENaC at both proximal and more prominently distal cleavage sites of its α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.
AU  - Bohnert, B.N.
AU  - Essigke, D.*
AU  - Janessa, A.*
AU  - Schneider, J.C.*
AU  - Wörn, M.*
AU  - Kalo, M.Z.*
AU  - Xiao, M.*
AU  - Kong, L.*
AU  - Omage, K.*
AU  - Hennenlotter, J.*
AU  - Amend, B.*
AU  - Birkenfeld, A.L.
AU  - Artunc, F.
C1  - 62888
C2  - 51143
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - F480-F493
TI  - Experimental nephrotic syndrome leads to proteolytic activation of the epithelial sodium channel (ENaC) in the mouse kidney.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 321
IS  - 4
PB  - Amer Physiological Soc
PY  - 2021
SN  - 1931-857X
ER  - 

TY  - JOUR
AB  - The current paradigm regarding sodium handling in animals and humans postulates that total body sodium is regulated predominately via regulation of extracellular volume. Active sodium storage independent of volume retention is thought to be negligible. However, studies in animals, hypertensive patients and healthy humans suggest non-osmotic storage of sodium in skin. We hypothesized that tissue sodium concentrations ([Na]T) found in humans vary and reflect regulation due to variable glycosaminoglycan content due to variable expression of XYLT-1. 27 patients on dialysis and 21 living kidney transplant donors free of clinically detectable edema were studied. During surgery, abdominal skin, muscle and arteries were biopsied. [Na]T was determined by inductively coupled plasma - optical emission spectrometry, semiquantitative glycosaminoglycan content with Alcian stain, XYLT-1 expression by real-time PCR. [Na]T of arteries were ranging between 0.86 and 9.83 g/kg wet weight and were significantly higher in arteries (4.52 ± 1.82 g/kg) than in muscle (2.03 ± 1.41 g/kg; p<0.001) or skin (3.24 ± 2.26 g/kg wet weight; p=0.038). For individual patients [Na]T correlated for skin and arterial tissue (r=0.440, p=0.012). [Na]T also correlated significantly with blinded semiquantitative analysis of glycosaminoglycans staining (r=0.588, p=0.004). In arteries XYLT-1 expression was also correlated with [Na]T (r=0.392, p=0.003). Our data confirm highly variable [Na]T in human skin and muscle and extend this observation to [Na]T in human arteries. These data support the hypothesis of water-independent sodium storage via regulated glycosaminoglycan synthesis in human tissues, including arteries.
AU  - Fischereder, M.*
AU  - Michalke, B.
AU  - Schmoeckel, E.*
AU  - Habicht, A.*
AU  - Kunisch, R.*
AU  - Pavelic, I.*
AU  - Szabados, B.*
AU  - Schönermarck, U.*
AU  - Nelson, P.*
AU  - Stangl, M.*
C1  - 51011
C2  - 43055
CY  - Bethesda
SP  - F319-F325
TI  - Sodium storage in human tissues is mediated by glycosaminoglycan expression.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 313
IS  - 2
PB  - Amer Physiological Soc
PY  - 2017
SN  - 1931-857X
ER  - 

TY  - JOUR
AB  - Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 weeks the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.
AU  - Mulay, S.R.*
AU  - Eberhard, J.N.*
AU  - Pfann, V.*
AU  - Marschner, J.A.
AU  - Darisipudi, M.N.*
AU  - Daniel, C.*
AU  - Romoli, S.*
AU  - Desai, J.*
AU  - Grigorescu, M.*
AU  - Kumar, S.V.*
AU  - Rathkolb, B.*
AU  - Wolf, E.*
AU  - Hrabě de Angelis, M.
AU  - Bäuerle, T.*
AU  - Dietel, B.*
AU  - Wagner, C.A.*
AU  - Amann, K.*
AU  - Eckardt, K.U.*
AU  - Aronson, P.S.*
AU  - Anders, H.J.*
AU  - Knauf, F.*
C1  - 47691
C2  - 39568
CY  - Bethesda
SP  - F785-F795
TI  - Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 310
IS  - 8
PB  - Amer Physiological Soc
PY  - 2016
SN  - 1931-857X
ER  - 

TY  - JOUR
AB  - The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene (SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1(I299F) exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid excretion is twofold lower. In contrast to hyperreninemia present in human disease, plasma renin concentration in homozygotes is not increased. The polyuria observed in homozygotes may be due to the combination of two additive factors, a decrease in activity of mutant NKCC2 and an increase in medullary blood flow, due to prostaglandin-induced vasodilation, that impairs countercurrent exchange of urea in the medulla. In conclusion, this novel viable mouse line with a missense Slc12a1 mutation exhibits most of the features of type I Bartter syndrome and may represent a new model for the study of this human disease.
AU  - Kemter, E.*
AU  - Rathkolb, B.*
AU  - Bankir, L.*
AU  - Schrewe, A.
AU  - Hans, W.
AU  - Landbrecht, C.*
AU  - Klaften, M.
AU  - Ivandic, B.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Wanke, R.*
AU  - Aigner, B.*
C1  - 3228
C2  - 27278
SP  - F1405-F1415
TI  - Mutation of the Na⁺-K⁺-2Cl‾ cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 298
IS  - 6
PB  - American Physiological Soc.
PY  - 2010
SN  - 1931-857X
ER  - 

TY  - JOUR
AB  - Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed Umod(A227T) exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid, and a selective defect in concentrating urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid, and energy metabolism are indirectly affected in heterozygous and homozygous mutant Umod(A227T) mice, manifesting in reduced body weight, fat mass, and metabolic rate as well as reduced blood cholesterol, triglycerides, and nonesterified fatty acids. In conclusion, Umod(A227T) might act as a gain-of-toxic-function mutation. Therefore, the Umod(A227T) mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy, and lipid metabolism.
AU  - Kemter, E.*
AU  - Rathkolb, B.*
AU  - Rozman, J.*
AU  - Hans, W.
AU  - Schrewe, A.*
AU  - Landbrecht, C.*
AU  - Klaften, M.*
AU  - Ivandic, B.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Klingenspor, M.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Wanke, R.*
AU  - Aigner, B.*
C1  - 716
C2  - 26598
CY  - Bethesda
SP  - F1391-F1398
TI  - Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 297
IS  - 5
PB  - American Physiological Society
PY  - 2009
SN  - 1931-857X
ER  - 

TY  - JOUR
AB  - Kidney diseases lead to the failure of urinary excretion of metabolism products. In the Munich ethylnitrosourea (ENU) mouse mutagenesis project, which is done on a C3H inbred genetic background, blood samples of more than 15,000 G1 offspring and 500 G3 pedigrees were screened for alterations in clinical-chemical parameters. We identified 44 animals consistently exhibiting increased plasma urea concentrations. Transmission analysis of the altered phenotype of 23 mice to subsequent generations led to the establishment of five mutant lines. Both sexes were affected in these lines. Urinary urea levels were decreased in the mutants. In addition, most mutants showed increased plasma and decreased urinary creatinine levels. Pathological investigation of kidneys from the five mutant lines revealed a broad spectrum of alterations, ranging from no macroscopic and light microscopic kidney alterations to decreased kidney weight-to-body weight ratio, dilation of the renal pelvis, and severe glomerular lesions. Thus screening for elevated plasma urea levels in a large-scale ENU mouse mutagenesis project resulted in the successful establishment of mouse strains which are valuable tools for molecular studies of mechanisms involved in urea excretion or which represent interesting models for kidney diseases.
AU  - Aigner, B.*
AU  - Rathkolb, B.*
AU  - Herbach, N.*
AU  - Kemter, E.*
AU  - Schessl, C.*
AU  - Klaften, M.
AU  - Klempt, M.*
AU  - Hrabě de Angelis, M.
AU  - Wanke, R.*
AU  - Wolf, E.*
C1  - 5843
C2  - 24536
SP  - 1560-1567
TI  - Screening for increased plasma urea levels in a large-scale ENU mouse mutagenesis project reveals kidney disease models.
JO  - Am. J. Physiol.-Renal Physiol.
VL  - 292
IS  - 5
PB  - American Physiological  Society
PY  - 2007
SN  - 1931-857X
ER  -