Epigenetic and non-epigenetic regulation of Klotho in kidney disease

Klotho is a novel renoprotective anti-aging protein available in membrane-bound or soluble form. Klotho is expressed in brain, pancreas, and other solid organs but shows highest expression levels in the kidney. Klotho sustains normal kidney physiology but Klotho regulation also contributes to the progression of kidney disease. Systemic and intrarenal levels of Klotho fall drastically during acute kidney injury, kidney fibrosis, diabetic nephropathy, and other forms of chronic kidney disease, etc. Moreover, exogenous supplementation or overexpression of endogenous Klotho attenuates kidney disease. The regulation of endogenous Klotho expression involves epigenetic as well as non-epigenetic mechanisms. The epigenetic modifications such as DNA methylation, post-translational histone modifications, miRNAs regulate the change in Klotho expression in kidney disease. Non-epigenetic mechanisms such as ER stress, Wnt signaling, activation of the renin angiotensin system (RAS), excessive reactive oxygen species and cytokine generation, albumin overload, and PPAR-γ signaling also contribute to Klotho regulation. Evolving evidence highlight the capacity of natural products to regulate Klotho expression in kidney disease. All these preclinical data suggest that Klotho could be a novel biomarker as well as therapeutic target. Here we review the different mechanisms of Klotho regulation in the context of Klotho as a biomarker and potential therapeutic agent.