KLOTHO methylation is linked to uremic toxins and chronic kidney disease

Abstract

Epigenetic regulation plays a major role in uremic toxin-induced chronic kidney disease (CKD) progression. The KLOTHO protein is a key modulator of homeostasis in renal function. Uremic toxin accumulation can induce DNA methyltransferase (DNMT) protein expression, which is involved in the silencing of KLOTHO through hypermethylation. Treatment with DNMT inhibitors can induce a hypermethylated status of KLOTHO and suppress mRNA and protein expression. Epigenetic targeting of specific genes may become an effective strategy to prevent progression of uremia-related CKD.

Effects of L-Carnitine on Mineral Metabolism in the Multicentre, Randomized, Double Blind, Placebo-Controlled CARNIDIAL Trial

“…This low Klotho state is related to renal function loss and contributes to hyperphosphatemia. The role of uremic toxins indoxylsulfate and p-cresol on the hypermethylation of the Klotho gene has also been recently evidenced [16] as the role of inflammation, angiotensin II and vitamin D deficiency [11]. In the absence of αKlotho expression, FGF23 has no effect on the parathyroid tissue where it normally inhibits the parathyroid cells proliferation and decreases PTH mRNA transcription and protein secretion [16].…”

Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

“…It has been shown that epigenetic processes such as methylation and acetylation in the Klotho gene promoter can modulate endogenous Klotho expression. In CKD, accumulated indoxyl sulfate or p-cresyl sulfate in the blood induces hypermethylation of the Klotho gene and decreased Klotho expression in CKD [81,82] . The hyperacetylation of histone in the Klotho promoter also inhibits Klotho expression [83] .…”

DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

“…27 Preliminary research evidence provides support for the importance of differential methylation in CKD. [28][29][30] We describe a relatively large-scale case-control study that aimed to quantitatively identify changes in DNA methylation with single site resolution associated with CKD.…”