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

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.

Automated summary

The study revealed that chronic angiotensin II-induced hypertension inhibits autophagy in mouse glomeruli, leading to accelerated podocyte injury when autophagy-related gene Atg5 is deleted. However, transgenic mice expressing the endogenous calpain inhibitor calpastatin showed higher podocyte autophagy and resistance to angiotensin II-induced inhibition, demonstrating a potential protective effect against podocyte damage and albuminuria. These findings suggest that preventing calpain-mediated inhibition of autophagy may offer a new therapeutic strategy for nephropathies associated with high renin-angiotensin system activity.