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Shahzad, K.* ; Fatima, S.* ; Al-Dabet, M.M.* ; Gadi, I.* ; Khawaja, H.* ; Ambreen, S.* ; Elwakiel, A.* ; Klöting, N. ; Blüher, M. ; Nawroth, P.* ; Mertens, P.* ; Michel, S.* ; Jaschinski, F.* ; Klar, R.* ; Isermann, B.*

CHOP-ASO ameliorates glomerular and tubular damage on top of ACE inhibition in diabetic kidney disease.

J. Am. Soc. Nephrol. 32, 3066-3079 (2021)
Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Chronic Kidney Disease ; Chronic Nephropathy ; Diabetic Nephropathy; Endoplasmic-reticulum-stress; Antisense Oligonucleotides; Er Stress; Mice; Apoptosis; Protects; Cells; Inflammation; Nephropathy; Therapy
ISSN (print) / ISBN 1046-6673
e-ISSN 1533-3450
Journal Journal of the American Society of Nephrology
Quellenangaben Volume: 32, Issue: 12, Pages: 3066-3079 Article Number: , Supplement: ,
Publisher American Society of Nephrology
Publishing Place 1725 I St, Nw Ste 510, Washington, Dc 20006 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants Secarna Pharmaceuticals GmbH Co.
Deutsche Forschungsgemeinschaft