NEWS ! The team is recruiting a post-doctoral fellow to work on cell metabolism in kidney inflammation. Post-doc in team 8
Our team consists of three groups, two in basic and one in clinical research : the Camerer group studies functions of G protein- coupled receptors (GPCRs) in vascular development and disease, and the Tharaux group studies the role of GPCRs and receptor tyrosine kinases (RTKs) in pathologies that arise secondary to glomerular capillary dysfunctions or cause them. We have a common interest in how these receptor families regulate vascular integrity and how loss of vascular integrity exacerbates inflammatory disease, and we both use genetic and pharmacological tools to address these questions in mouse models. We closely work with the Department of Nephrology directed by Eric Thervet at the Hôpital Européen Georges-Pompidou on translational aspects. Our main scientific goals are to : 1. Identify roles for and mechanisms of GPCR signaling in development and disease, 2. Improve our understanding of the pathogenesis of vascular and glomerular diseases (primarily focal segmental glomerulosclerosis (FSGS), Sickle cell nephropathy, crescentic rapidly progressive glomerulonephritis (RPGN), diabetic nephropathy) with endothelial and podocyte damage, with emphasis on pathological crosstalk between GPCRs and RTKs, 3. Identify critical switches in the pathogenesis of glomerular diseases with focus on GPCRs and RTKs.
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.More