2.2.8. Epigenetic Modifications

Several factors such as uremic toxins, oxidative stress, and inflammation increase the prevalence of epigenetic changes and enhance the progression to CKD [65,66]. Inflammation, a major factor in the pathogenesis of CKD, correlates with global DNA methylation [67]. Indeed, a significant association has been identified between DNA methylation and the prevalence and incidence of CKD [66]. Experimental studies observed that hypomethylation in the promoter region of the connective tissue growth factor (*ctgf*) gene is associated with reduced GFR and declined renal function [68]. Data from experimental studies in rats and mice indicate that altered DNA methylation is an important mechanism that initiates the transition from AKI to CKD [69]. In models of unilateral ureteral obstruction (UUO), it was observed that hypermethylation of the Klotho promoter by TGFβ decreased Klotho protein expression, which led to tubular and interstitial fibrosis. Similarly, hypermethylation of the *Vegfa* gene promoter led to reduced VEGF-A signaling, which can lead to capillary collapse and subsequent hypoxia and fibrosis [70]. In ischemic

reperfusion rat models, aberrant methylation of the complement C3 promoter region in tubular epithelial cells activated the complement system. This is strongly associated with inflammation and accelerated renal decline [63,71]. Other studies showed that complement component, C5a, promotes DNA hypomethylation of several genes that have integral roles in the initiating cell cycle arrest and senescence [63]. Aberrant hypermethylation of laminin genes has been reported to cause the development of glomerulosclerosis and tubulointerstitial fibrosis in older kidneys, while aberrant methylation of the *rasal1* (Ras protein activator-like 1) gene induced the activation of the Ras–GTPase pathway in fibroblasts, leading to proliferation and fibrosis [72].

In addition to DNA methylation, numerous studies suggest that RNA interference via microRNA (miRNA) is a key factor involved in the pathogenesis and progression of CKD [73]. Several miRNAs, which are involved in post-transcriptional regulation of gene expression, have been linked to inflammation and fibrosis and may enhance the progression of CKD [66,74,75]. One of the most studied miRNAs is miR-192, which plays a role in the expression of profibrotic genes [75]. Upregulated expression of miR-192 leads to the activation of TGF-β and Smad3 signaling pathways, which lead to renal fibrosis through the deposition of collagen and fibronectin [75]. Similarly, the activation of TGF-β pathways increases histone methylation and increased expression of genes involved in deposition of extracellular matrix proteins [75].
