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The anti-aging gene, klotho, has been identified as a multi-functional humoral factor and is implicated in multiple biological processes. However, the effects of klotho on podocyte injury in diabetic nephropathy are poorly understood. Thus, the current study aims to investigate the renoprotective effects of klotho against podocyte injury in diabetic nephropathy. We examined lipid accumulation and klotho expression in the kidneys of diabetic patients and animals. We stimulated cultured mouse podocytes with palmitate to induce lipotoxicity-mediated podocyte injury with or without recombinant klotho. Klotho level was decreased in podocytes of lipid-accumulated obese diabetic kidneys and palmitate-treated mouse podocytes. Palmitate-treated podocytes showed increased apoptosis, intracellular ROS, ER stress, inflammation, and fibrosis, and these were significantly attenuated by klotho administration. Klotho treatment restored palmitate-induced downregulation of the antioxidant molecules, Nrf2, Keap1, and SOD1. Klotho inhibited the phosphorylation of FOXO3a, promoted its nuclear translocation, and then upregulated MnSOD expression. In addition, klotho administration attenuated palmitate-induced cytoskeleton changes, decreased nephrin expression, and increased TRPC6 expression, eventually improving podocyte albumin permeability. These results suggest that klotho administration prevents palmitate-induced functional and morphological podocyte injuries, and this may indicate that klotho is a potential therapeutic agent for the treatment of podocyte injury in obese diabetic nephropathy.

OBJECTIVE: Although α-klotho is known as an anti-aging, antioxidant, and cardio-renal protective protein, the clinical implications of soluble α-klotho levels in patients with diabetes have not been evaluated. Therefore, this study evaluated whether plasma and urinary α-klotho levels are associated with albuminuria in kidney disease in diabetes. RESEARCH DESIGN AND METHODS: A total of 147 patients with type 2 diabetes and 25 healthy control subjects were enrolled. The plasma and urine concentrations of α-klotho were analyzed by enzyme-linked immunosorbent assay. RESULTS: Plasma α-klotho (572.4 pg/mL [95% CI, 541.9-604.6 pg/mL] vs. 476.9 pg/mL [95% CI, 416.9-545.5 pg/mL]) and urinary α-klotho levels (59.8 pg/mg creatinine [95% CI, 43.6-82.0 pg/mg creatinine] vs. 21.0 pg/mg creatinine [95% CI, 9.7-45.6 pg/mg creatinine]) were significantly higher in diabetic patients than non-diabetic controls. Among diabetic patients, plasma α-klotho concentration was inversely associated with albuminuria stages (normoalbuminuria, 612.6 pg/mL [95% CI, 568.9-659.6 pg/mL], microalbuminuria, 551.8 pg/mL [95% CI, 500.5-608.3 pg/mL], and macroalbuminuria, 505.7 pg/mL [95% CI, 439.7-581.7 pg/mL] (p for trend = 0.0081), while urinary α-klotho levels were remained constantly high with increasing urinary albumin excretion. CONCLUSIONS: Soluble α-klotho levels in plasma and urine may be novel and useful early markers of diabetic renal injury.