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Novel soluble guanylyl cyclase activators increase glomerular cGMP, induce vasodilation and improve blood flow in the murine kidney.

Authors
  • Stehle, Daniel1
  • Xu, Min Ze2
  • Schomber, Tibor3
  • Hahn, Michael G3
  • Schweda, Frank4
  • Feil, Susanne1
  • Kraehling, Jan R3
  • Eitner, Frank3, 5
  • Patzak, Andreas2
  • Sandner, Peter3, 6
  • Feil, Robert1
  • Bénardeau, Agnès3, 7
  • 1 Interfakultäres Institut für Biochemie (IFIB), University of Tübingen, Tübingen, Germany. , (Germany)
  • 2 Institute of Vegetative Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. , (Germany)
  • 3 Bayer AG, Cardiovascular Research, Pharma Research Center, Wuppertal, Germany. , (Germany)
  • 4 Institut für Physiologie, Universität Regensburg, Regensburg, Germany. , (Germany)
  • 5 Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany. , (Germany)
  • 6 Institute of Pharmacology, Hannover Medical School, Hannover, Germany. , (Germany)
  • 7 Novo Nordisk A/S, Cardio-Renal Biology, Måløv, Denmark. , (Denmark)
Type
Published Article
Journal
British Journal of Pharmacology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jun 01, 2022
Volume
179
Issue
11
Pages
2476–2489
Identifiers
DOI: 10.1111/bph.15586
PMID: 34096053
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Generation of cGMP via NO-sensitive soluble guanylyl cyclase (sGC) has been implicated in the regulation of renal functions. Chronic kidney disease (CKD) is associated with decreased NO bioavailability, increased oxidative stress and oxidation of sGC to its haem-free form, apo-sGC. Apo-sGC cannot be activated by NO, resulting in impaired cGMP signalling that is associated with chronic kidney disease progression. We hypothesised that sGC activators, which activate apo-sGC independently of NO, increase renal cGMP production under conditions of oxidative stress, thereby improving renal blood flow (RBF) and kidney function. Two novel sGC activators, runcaciguat and BAY-543, were tested on murine kidney. We measured cGMP levels in real time in kidney slices of cGMP sensor mice, vasodilation of pre-constricted glomerular arterioles and RBF in isolated perfused kidneys. Experiments were performed at baseline conditions, under L-NAME-induced NO deficiency, and in the presence of oxidative stress induced by ODQ. Mouse glomeruli showed NO-induced cGMP increases. Under baseline conditions, sGC activator did not alter glomerular cGMP concentration or NO-induced cGMP generation. In the presence of ODQ, NO-induced glomerular cGMP signals were markedly reduced, whereas sGC activator induced strong cGMP increases. L-NAME and ODQ pretreated isolated glomerular arterioles were strongly dilated by sGC activator. sGC activator also increased cGMP and RBF in ODQ-perfused kidneys. sGC activators increase glomerular cGMP, dilate glomerular arterioles and improve RBF under disease-relevant oxidative stress conditions. Therefore, sGC activators represent a promising class of drugs for chronic kidney disease treatment. This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc. © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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