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

Abstract

BACKGROUND AND PURPOSEMitochondrial 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 APPROACHThe 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 RESULTSTDZD-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 IMPLICATIONSOur 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.

Genetic and Pharmacologic Targeting of Glycogen Synthase Kinase 3β Reinforces the Nrf2 Antioxidant Defense against Podocytopathy

“…Indeed, other mechanisms, such as suppression of proinflammatory NFkB activation and desensitization of mitochondria permeability transition, have been implicated, at least in part, in the podocyte protective effect following GSK3b inhibition. 32,51 In summary, targeted inhibition of GSK3b in podocytes via conditional KO or pharmacologic blockade reinforced the Nrf2 antioxidant response after doxorubicin or NTS insult, alleviated podocytopathy and glomerular injury and attenuated proteinuria. Our study suggests that the GSK3b-regulated Nrf2 cell defense pathway in glomerular podocytes might serve as a novel and feasible therapeutic target for proteinuric glomerulopathies.…”

The Emerging Role of Mitochondrial Targeting in Kidney Disease

“…The GSK3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) confers protection against podocyte injury in a murine model of adriamycin-induced AKI (Wang et al 2015b). Likewise, TDZD-8 diminishes mitochondrial permeability transition, improves acute kidney dysfunction, and ameliorates tubular injury in mice with nonsteroidal anti-inflammatory drug-induced AKI (Bao et al 2012), suggesting GSK3β inhibition as adjunct therapy in drug-induced AKI.…”

Remote Ischemic Preconditioning for Kidney Protection: GSK3β-Centric Insights Into the Mechanism of Action

“…Kidney cells have a discrete mitochondrial pool of GSK3β 48,58,59 . Components of the mitochondria permeability transition (MPT) pore, including cyclophilin F and the voltage-dependent anion channel (VDAC), possess GSK3β phosphorylation consensus motifs and serve as putative substrates for GSK3β 48,58–61 .…”