Proteinuric conditions demonstrate structural and compositional changes of the foot processes and slit diaphragms between podocytes. β-Catenin in podocytes serves as an adapter protein anchoring P-cadherin of slit diaphragms to actin filaments of the podocyte cytoskeleton. To investigate the effect of ginseng total saponin (GTS) on pathologic changes of podocyte P-cadherin/β-catenin unit induced by diabetic conditions, we cultured mouse podocytes under: 1) normal glucose (5 mM, = control); 2) high glucose (HG, 30 mM); 3) advanced glycosylation end products (AGE)-added; or 4) HG plus AGE-added conditions and treated with GTS. In confocal imaging, β-catenin colocalized with P-cadherin predominantly at intercellular junction area. However, diabetic conditions relocalized and concentrated both molecules at perinuclear cytoplasmic area. In Western blotting, diabetic conditions, especially HG plus AGE-added condition, also decreased cellular β-catenin protein levels at 6, 24, and 48 hours. GTS improved such quantitative and qualitative changes of β-catenin. These findings imply that HG plus AGE have an influence on the redistribution and amount of P-cadherin/ β-catenin unit of podocytes, which can be reversed by GTS.

As a sensor of cellular energy status, AMP-activated protein kinase (AMPK) plays an important role in the pathophysiology of diabetes and its complications. Because AMPK is also expressed in podocytes, podocyte AMPK would be an important factor contributing to development of podocyte injury. We investigated the roles of AMPK in the pathological changes of podocyte synaptopodin induced by angiotensin II (Ang II), a major injury inducer. Mouse podocytes were incubated in media containing various concentrations of Ang II and AMPK-modulating agents, and the changes of synaptopodin were analyzed by confocal imaging and Western blotting. Ang II and compound C, an AMPK inhibitor, concentrated and re-localized synaptopodin from peripheral cytoplasm to the internal cytoplasm portion in podocytes. Ang II also reduced synaptopodin protein and mRNA, which were reversed by metformin and 5-aminoimidazole-4-carboxamide ribonucleoside. Losartan, an Ang II type 1 receptor antagonist, also recovered synaptopodin mRNA, which was suppressed by Ang II. We suggest that Ang II induces the relocation and suppression of podocyte synaptopodin by suppression of AMPK and via Ang II type 1 receptor, which would be an important mechanism in Ang II-induced podocyte phenotypical changes.