Pharmacological targeting of GSK3β confers protection against podocytopathy and proteinuria by desensitizing mitochondrial permeability transition.

BACKGROUND AND PURPOSE: Mitochondrial dysfunction, triggered by mitochondria permeability transition (MPT), has been centrally implicated in the pathogenesis of podocytopathy and involves a multitude of cell signalling mechanisms, among which, glycogen synthase kinase (GSK) 3β has emerged as the integration point and plays a crucial role. This study aimed to examine the role of GSK3β in podocyte MPT and mitochondrial dysfunction.

EXPERIMENTAL APPROACH: The regulatory effect of GSK3β on MPT was examined in differentiated podocytes in culture and in a murine model of adriamycin-induced podocytopathy using 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a highly selective small-molecule inhibitor of GSK3β.

KEY RESULTS: TDZD-8 therapy prominently ameliorated the proteinuria and glomerular sclerosis in mice with adriamycin nephropathy; this was associated with a correction of GSK3β overactivity in the glomerulus and attenuation of podocyte injuries, including foot process effacement and podocyte death. Consistently, in adriamycin-injured podocytes, TDZD-8 treatment counteracted GSK3β overactivity, improved cell viability and prevented death, concomitant with diminished oxidative stress, improved mitochondrial dysfunction and desensitized MPT. Mechanistically, a discrete pool of GSK3β was found in podocyte mitochondria, which interacted with and phosphorylated clyclophilin F, a key structural component of the MPT pore. TDZD-8 treatment prevented the GSK3β-controlled phosphorylation and activation of cyclophilin F, desensitized MPT and alleviated the damage to mitochondria in podocytes induced by adriamycin in vivo and in vitro.

CONCLUSIONS AND IMPLICATIONS: Our findings suggest that pharmacological targeting of GSK3β could represent a promising and feasible therapeutic strategy for protecting podocytes against mitochondrial dysfunction induced by oxidative injuries.