Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy.

Autor:	Salemkour Y; Université Paris Cité, Inserm, PARCC, Paris, France., Yildiz D; Department of Nephrology, Research Institute of Medical Innovations, Radboud University Medical Centre, Nijmegen, The Netherlands., Dionet L; Université Paris Cité, Inserm, PARCC, Paris, France., 't Hart DC; Department of Nephrology, Research Institute of Medical Innovations, Radboud University Medical Centre, Nijmegen, The Netherlands., Verheijden KAT; Department of Nephrology, Research Institute of Medical Innovations, Radboud University Medical Centre, Nijmegen, The Netherlands., Saito R; Discovery Technology Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan., Mahtal N; Université Paris Cité, Inserm, PARCC, Paris, France., Delbet JD; Université Paris Cité, Inserm, PARCC, Paris, France.; Pediatric Nephrology Department, Armand Trousseau Hospital, DMU Origyne, APHP, Paris and French Reference Center for Rare Diseases MARHEA, Paris, France., Letavernier E; Sorbonne Université, Hôpital Tenon, Paris, France.; INSERM UMR S 1155, Hôpital Tenon, Paris, France.; Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France., Rabant M; Pathology Department, Necker-Enfants Malades Hospital - Paris, Paris, France., Karras A; Université Paris Cité, Inserm, PARCC, Paris, France.; Nephrology Unit, Georges Pompidou European Hospital - Paris, Paris, France., van der Vlag J; Department of Nephrology, Research Institute of Medical Innovations, Radboud University Medical Centre, Nijmegen, The Netherlands., Nijenhuis T; Department of Nephrology, Research Institute of Medical Innovations, Radboud University Medical Centre, Nijmegen, The Netherlands., Tharaux PL; Université Paris Cité, Inserm, PARCC, Paris, France., Lenoir O; Université Paris Cité, Inserm, PARCC, Paris, France.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2023 Nov 01; Vol. 34 (11), pp. 1823-1842. Date of Electronic Publication: 2023 Sep 06.
DOI:	10.1681/ASN.0000000000000212
Abstrakt:	Significance Statement: Autophagy protects podocytes from injury in diabetic kidney disease (DKD). Restoring glomerular autophagy is a promising approach to limit DKD. This study demonstrates a novel regulatory mechanism of autophagy that blocks this critical protection of the glomerular filtration barrier. We demonstrated that TRPC6 induced in podocytes in mouse models of diabetes mediates calpain activation, thereby impairing podocyte autophagy, causing injury and accelerating DKD. Furthermore, this study provides proof of principle for druggable targets for DKD because restoration of podocyte autophagy by calpain inhibitors effectively limits glomerular destruction. Background: Diabetic kidney disease is associated with impaired podocyte autophagy and subsequent podocyte injury. The regulation of podocyte autophagy is unique because it minimally uses the mTOR and AMPK pathways. Thus, the molecular mechanisms underlying the impaired autophagy in podocytes in diabetic kidney disease remain largely elusive. Methods: This study investigated how the calcium channel TRPC6 and the cysteine protease calpains deleteriously affect podocyte autophagy in diabetic kidney disease in mice. We demonstrated that TRPC6 knockdown in podocytes increased the autophagic flux because of decreased cysteine protease calpain activity. Diabetic kidney disease was induced in vivo using streptozotocin with unilateral nephrectomy and the BTBR ob/ob mouse models. Results: Diabetes increased TRPC6 expression in podocytes in vivo with decreased podocyte autophagic flux. Transgenic overexpression of the endogenous calpain inhibitor calpastatin, as well as pharmacologic inhibition of calpain activity, normalized podocyte autophagic flux, reduced nephrin loss, and prevented the development of albuminuria in diabetic mice. In kidney biopsies from patients with diabetes, we further confirmed that TRPC6 overexpression in podocytes correlates with decreased calpastatin expression, autophagy blockade, and podocyte injury. Conclusions: Overall, we discovered a new mechanism that connects TRPC6 and calpain activity to impaired podocyte autophagy, increased podocyte injury, and development of proteinuria in the context of diabetic kidney disease. Therefore, targeting TRPC6 and/or calpain to restore podocyte autophagy might be a promising therapeutic strategy for diabetic kidney disease. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
Databáze:	MEDLINE
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