Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury

Increased expression and activity of the Ca<sup>2+</sup> channel transient receptor potential channel 6 (TRPC6) is associated with focal segmental glomerulosclerosis, but therapeutic strategies to target TRPC6 are currently lacking. Nitric oxide (NO) is crucial for normal glomerular func...

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Autores principales:	Daan ‘t Hart, Jinhua Li, Johan van der Vlag, Tom Nijenhuis
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Riociguat nitric oxide TRPC6 podocyte injury focal segmental glomerulosclerosis Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/a45688733fae4db5a1afba740a6cc76c
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spelling	oai:doaj.org-article:a45688733fae4db5a1afba740a6cc76c2021-11-25T17:57:12ZRepurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury10.3390/ijms2222124851422-00671661-6596https://doaj.org/article/a45688733fae4db5a1afba740a6cc76c2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12485https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Increased expression and activity of the Ca<sup>2+</sup> channel transient receptor potential channel 6 (TRPC6) is associated with focal segmental glomerulosclerosis, but therapeutic strategies to target TRPC6 are currently lacking. Nitric oxide (NO) is crucial for normal glomerular function and plays a protective role in preventing glomerular diseases. We investigated if NO prevents podocyte injury by inhibiting injurious TRPC6-mediated signaling in a soluble guanylate cyclase (sGC)-dependent manner and studied the therapeutic potential of the sGC stimulator Riociguat. Experiments were performed using human glomerular endothelial cells and podocytes. Podocyte injury was induced by Adriamycin incubation for 24 h, with or without the NO-donor S-Nitroso-N-acetyl-DL-penicillamine (SNAP), the sGC stimulator Riociguat or the TRPC6 inhibitor Larixyl Acetate (LA). NO and Riociguat stimulated cGMP synthesis in podocytes, decreased Adriamycin-induced TRPC6 expression, inhibited the Adriamycin-induced TRPC6-mediated Ca<sup>2+</sup> influx and reduced podocyte injury. The protective effects of Riociguat and NO were blocked when sGC activity was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or when TRPC6 activity was inhibited by LA. Our data demonstrate a glomerular (e)NOS-NO-sGC-cGMP-TRPC6 pathway that prevents podocyte injury, which can be translated to future clinical use by, e.g., repurposing the market-approved drug Riociguat.Daan ‘t HartJinhua LiJohan van der VlagTom NijenhuisMDPI AGarticleRiociguatnitric oxideTRPC6podocyte injuryfocal segmental glomerulosclerosisBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12485, p 12485 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Riociguat nitric oxide TRPC6 podocyte injury focal segmental glomerulosclerosis Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Riociguat nitric oxide TRPC6 podocyte injury focal segmental glomerulosclerosis Biology (General) QH301-705.5 Chemistry QD1-999 Daan ‘t Hart Jinhua Li Johan van der Vlag Tom Nijenhuis Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
description	Increased expression and activity of the Ca<sup>2+</sup> channel transient receptor potential channel 6 (TRPC6) is associated with focal segmental glomerulosclerosis, but therapeutic strategies to target TRPC6 are currently lacking. Nitric oxide (NO) is crucial for normal glomerular function and plays a protective role in preventing glomerular diseases. We investigated if NO prevents podocyte injury by inhibiting injurious TRPC6-mediated signaling in a soluble guanylate cyclase (sGC)-dependent manner and studied the therapeutic potential of the sGC stimulator Riociguat. Experiments were performed using human glomerular endothelial cells and podocytes. Podocyte injury was induced by Adriamycin incubation for 24 h, with or without the NO-donor S-Nitroso-N-acetyl-DL-penicillamine (SNAP), the sGC stimulator Riociguat or the TRPC6 inhibitor Larixyl Acetate (LA). NO and Riociguat stimulated cGMP synthesis in podocytes, decreased Adriamycin-induced TRPC6 expression, inhibited the Adriamycin-induced TRPC6-mediated Ca<sup>2+</sup> influx and reduced podocyte injury. The protective effects of Riociguat and NO were blocked when sGC activity was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or when TRPC6 activity was inhibited by LA. Our data demonstrate a glomerular (e)NOS-NO-sGC-cGMP-TRPC6 pathway that prevents podocyte injury, which can be translated to future clinical use by, e.g., repurposing the market-approved drug Riociguat.
format	article
author	Daan ‘t Hart Jinhua Li Johan van der Vlag Tom Nijenhuis
author_facet	Daan ‘t Hart Jinhua Li Johan van der Vlag Tom Nijenhuis
author_sort	Daan ‘t Hart
title	Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
title_short	Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
title_full	Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
title_fullStr	Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
title_full_unstemmed	Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
title_sort	repurposing riociguat to target a novel paracrine nitric oxide-trpc6 pathway to prevent podocyte injury
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a45688733fae4db5a1afba740a6cc76c
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Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury

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