Translating fundamental insights in podocyte metabolism and cell cycle regulation: development of a new treatment for Stopping crescentic Immune Glomerulonephritis

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Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of renal function, with severe damage of glomeruli, the filtering units of the kidney through glomerular crescent formation (crescentshaped scars) seen on kidney biopsies. If left untreated, it rapidly progresses into acute renal failure and death within months. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents. Currently RPGN is treated with broad-spectrum immunosuppression causing remission of the immune injury achieved in the majority of patients. Nevertheless, risk of end- stage renal failure at 5 years is still near 30 %, with a number of patients developing chronic kidney disease (CKD). Moreover, such treatments are associated with significant morbidity due to infections and malignancy. ERC-supported efforts in our lab have unravelled local mediators and transcription factors that critically control the tolerance of intrinsic glomerular cells to inflammatory insult. My team has shown that the PPARγ (peroxisome proliferatoractivated receptors gamma) pathway is instrumental in the protection of the inflammatory response during immunecomplex mediated RPGN, in large part through protection of kidney cells, named podocytes. We now plan to move forward to transform this finding from our TARGET-GLOMDIS ERC grant into a clinically effective innovative therapy. We expect to bring original therapeutic effect by preventing podocytes death and dysfunction in addition to promoting anti-inflammatory actions. The STOPIG project represents a unique opportunity to provide proof-of-concept for a new and cost-effective therapy for patients with RPGN based on stimulation of PPARγ with repurposed pioglitazone.