Mineralocorticoid receptor inhibition in parietal epithelial cells prevents focal segmental glomerulosclerosis and crescentic glomerulonephritis

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INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is a common histological lesion in adults worldwide. It results from initial podocyte injury, followed by a maladaptive activation of glomerular parietal epithelial cells (PECs), which leads to progressive scarring of glomeruli. Abnormal PEC phenotype is also a hallmark of crescentic glomerulonephritides, another class of severe kidney diseases that complicate small vessel vasculitides. Current knowledge of the pathophysiological mechanisms leading to PEC activation is limited. Recent evidence indicates an active and destructive role for PECs in extra-capillary glomerular diseases. Therefore, targeting such maladaptive responses could represent a novel therapeutic option to prevent kidney failure in patients. Yet, druggable pathways to prevent or stop the pathogenic behavior of PECs are still elusive. METHODS: Here, we examined the role of the mineralocorticoid receptor signaling in PECs in two mouse models of glomerular disease involving PEC activation: a robust model of maladaptive FSGS with deoxycorticosterone acetate (DOCA)-salt administration with uninephrectomy, and nephrotoxic serum-induced crescentic glomerulonephritis. RESULTS: We demonstrate that targeting the mineralocorticoid receptor (MR) (Nr3c2) gene specifically in PECs prevents migration and proliferation after DOCA-salt administration with uninephrectomy. Remarkably, both MR deficiency in PECs and mineralocorticoid receptor pharmacological blockade using eplerenone were also effective in preventing extracapillary lesions and glomerular failure in nephrotoxic serum-induced crescentic glomerulonephritis. Additionally, we revealed a significant overlap between pathways triggered by heparin-binding EGF-like growth factor and its receptor signaling and MR signaling. This promoted the migration, proliferation, and epithelial-to-mesenchymal transition of PECs. CONCLUSIONS: Together, our results highlight the common role of MR signaling in the pathophysiology of extra-capillary glomerulopathies, FSGS, and crescentic glomerulonephritis. This supports the use of MR antagonists as potential complementary therapeutic agents with original modes of action for severe diseases.

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