Rac1/PAK1 signaling promotes epithelial-mesenchymal transition of podocytes in vitro via triggering β-catenin transcriptional activity under high glucose conditions.

Ras-related C3 botulinum toxin substrate 1 (Rac1), together with its major downstream effector p21-activated kinase 1 (PAK1), has been identified a central role in cellular events such as cell cytoskeletal remodeling that contributed to cell migration and epithelial-mesenchymal transition (EMT). And there are data implicating that podocytes underwent EMT under pathological conditions. However, little is known about mechanisms of podocytes undergoing EMT. To address this, we assessed the cellular changes of podocytes after high glucose stimulation in vitro, detected the effects of Rac1/PAK1 signaling on podocytes in response to the stimuli, and investigated interactions of Rac1/PAK1 axis with β-catenin and Snail under high glucose conditions. We found that in vitro high glucose treatment led to remarkable down-regulation of nephrin and P-cadherin, as well as significant up-regulation of α-SMA and FSP-1, suggesting that in the presence of high glucose, podocytes underwent EMT, during which Rac1/PAK1 signaling was activated. And these were notably ameliorated by Rac1 gene knockdown. Furthermore, β-catenin and Snail nuclear translocation were triggered by Rac1/PAK1 axis, which were both markedly reversed via Rac1 gene knockdown or pretreatment of IPA-3, a PAK1 inhibitor. These findings elaborated that Rac1/PAK1 signaling contributed to high glucose-induced podocyte EMT via promoting β-catenin and Snail transcriptional activities, which could be a potential mechanism involved in podocytes injury in response to stimuli under diabetic conditions.