CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease.

Autor:	Shahzad K; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany., Fatima S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany.; Institute of Experimental Internal Medicine, Department of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Al-Dabet MM; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany.; Department of Medical Laboratories, American University of Madaba, Amman, Jordan., Gadi I; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany., Khawaja H; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany., Ambreen S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany., Elwakiel A; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany., Klöting N; Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany., Blüher M; Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany.; Medical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital Leipzig, Leipzig, Germany., Nawroth PP; Internal Medicine I and Clinical Chemistry, German Diabetes Center, Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany., Mertens PR; Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Department of Internal Medicine, Otto-von-Guericke University, Magdeburg, Germany., Michel S; Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany., Jaschinski F; Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany., Klar R; Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany., Isermann B; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2021 Dec 01; Vol. 32 (12), pp. 3066-3079. Date of Electronic Publication: 2021 Dec 01.
DOI:	10.1681/ASN.2021040431
Abstrakt:	Background: Maladaptive endoplasmic reticulum 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). Here, we determined whether locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD. Methods: We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study. We used renal functional parameters and morphologic analyses to assess the effect of CHOP-ASO and renal gene-expression profiling to identify 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 the 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. CHOP-ASO affected a significantly larger number of genes and disease pathways, including reduced sodium-glucose transport protein 2 (Slc5a2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented 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, particularly at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD. (Copyright © 2021 by the American Society of Nephrology.)
Databáze:	MEDLINE
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