Calpastatin prevents Angiotensin II–mediated podocyte injury through maintenance of autophagy - Archive ouverte HAL Access content directly
Journal Articles Kidney International Year : 2021

Calpastatin prevents Angiotensin II–mediated podocyte injury through maintenance of autophagy

(1) , (1) , (2) , (1) , (1) , (1) , (1) , (1) , (1) , (2) , (1) , (1) , (1)
1
2

Abstract

The strong predictive value of proteinuria in chronic glomerulopathies is firmly established as well as the pathogenic role of angiotensin II promoting progression of glomerular disease with an altered glomerular filtration barrier, podocyte injury and scarring of glomeruli. Here we found that chronic angiotensin II-induced hypertension inhibited autophagy flux in mouse glomeruli. Deletion of Atg5 (a gene encoding a protein involved autophagy) specifically in the podocyte resulted in accelerated angiotensin II-induced podocytopathy, accentuated albuminuria and glomerulosclerosis. This indicates that autophagy is a key protective mechanism in the podocyte in this condition. Angiotensin-II induced calpain activity in podocytes inhibits autophagy flux. Podocytes from mice with transgenic expression of the endogenous calpain inhibitor calpastatin displayed higher podocyte autophagy at baseline that was resistant to angiotensin II-dependent inhibition. Also, sustained autophagy with calpastatin limited podocyte damage and albuminuria. These findings suggest that hypertension has pathogenic effects on the glomerular structure and function, in part through activation of calpains leading to blockade of podocyte autophagy. These findings uncover an original mechanism whereby angiotensin II-mediated hypertension inhibits autophagy via calcium-induced recruitment of calpain with pathogenic consequences in case of imbalance by calpastatin activity. Thus, preventing a calpain-mediated decrease in autophagy may be a promising new therapeutic strategy for nephropathies associated with high renin-angiotensin system activity.
Fichier principal
Vignette du fichier
PIIS0085253821002660.pdf (5.53 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Loading...

Dates and versions

inserm-03788343 , version 1 (26-09-2022)

Identifiers

Cite

Imane Bensaada, Blaise Robin, Joëlle Perez, Yann Salemkour, Anna Chipont, et al.. Calpastatin prevents Angiotensin II–mediated podocyte injury through maintenance of autophagy. Kidney International, 2021, 100 (1), pp.90-106. ⟨10.1016/j.kint.2021.02.024⟩. ⟨inserm-03788343⟩

Collections

INSERM UP-SANTE
1 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More