Klotho and Renal Fibrosis

Implication for health policy/practice/research/medical education: Klotho is a newly discovered protein with pleotropic effects and have affected different fields of renal medicine from translational research to clinical nephrology. Here we want to summarize some new scopes in the field of renal fibrosis and Klotho with this hope that in future it could be implemented as a new therapeutic strategy to combat the renal fibrosis. Renal fibrosis is a pathological condition that characterized by excessive accumulation of extracellular matrix (ECM) and it is a common pathway of progression in different renal diseases including chronic glomerulone-phritis, diabetic nephropathy chronic allograft nephrop-athy and renal senescence (1, 2). In the process of renal fibrosis leukocyte infiltration, activation of fibroblasts and myofibroblasts, epithelial-mesenchymal transition (EMT) all have been identified as the major events (3). Behind The pathological features there are complex orchestrated interplay of different factors including cytokines (TGF-β, IFN-γ, IL-10), transcriptional activator factors (Sp1, Egr-1, Smad3), cell surface repressors down regulation or up regulation (Smad7, Fli-1, PPAR-γ, p53, Klotho) and epigenetic modulators (acetyltransferase, methyltrans-ferases, deacetylases, microRNAs) (4). Deregulation of pro-fibrotic and down regulation of anti-fibrotic factors play an important role in initiation and progression of renal fibrosis. Understanding the mechanism would be valuable to diagnose, prevent and even reverse the process of fibrosis. The role of micro RNA as a biomarker or as a therapeutic modality of renal fibrosis has recently be discussed by authors (5). Klotho, was first identified as an anti-aging protein in 1997, and it spawned two decades of aging research (6). Klotho is expressed in different tissues including kidney , heart, brain, and parathyroid but it is particularly highly expressed in kidney and predominantly in distal and proximal convoluted tubules. Klotho is a single-pass transmembrane (130 KDa) protein (6, 7). Membrane-anchored Klotho acts as a co-receptor for fibroblast growth factor-23 that promote renal phosphate excretion and suppresses active vitamin D synthesis (8, 9) soluble Klotho (70 kD) is generated from the Klotho gene through alternative splicing. It could also sheds from cell membrane (9). Soluble Klotho (sKl) acts as a hormonal with multiple renal and extrarenal functions including suppression of fibrosis (10), antioxidant activity (11), preservation of stem cells (12), down regulation of Wnt signal-ing and acting as an anti-aging agent (13) and modulation of ion transport (14). Klotho-deficient mice develop severe kidney damage and fibrosis. Kl −/− deficient mice with unilateral ureteral obstruction (UUO) had higher TGF-β1 levels and …