Methylation as an important epigenetic mechanism should be considered more in recurrent stone formations. Promoter hypermethylation of VRD and CLDN genes may have an essential role in recurrent kidney stones formations. We select vitamin D receptor (VDR), calcium-sensing receptor (CaSR), and claudin 14 (CLDN14) genes based on literature and meta-analysis. Only these three genes were studied in this work. This deficiency needs to be reflected. We select the genes that their gene expression regulation is controlled by promoter methylation. Because there is not previous study on methylation and just SNPs are discussed in Urolithiasis our study can be the good starting point for such studies. Renal stone formation risk factors have classically reflected environmental, geographic, and dietary issues, often based on population studies. Several treatment strategies are considered for the stone treatment depending on the stone size and skin-to-stone distance [9,10,11,12,13]. Moreover, the heritability of renal stones has also been proven. In twin studies, the estimated heritability of kidney stones was reported at 56%, and this has been supported by additional studies measuring the familial pattern of stones [14]. More recently, there has been a comprehensive exploration for rare monogenetic bases of renal stones by means of selected stone-forming populations [15,16,17].

Hypercalciuria is integral in the pathogenesis of stone formation that can be arise through calcium deposition in the renal papilla. The etiology of hypercalciuria is not well understood but includes augmented bone resorption, calcium hyperabsorption in the intestine, and lessen renal reabsorption. Calcium reabsorption happens mainly in the proximal tubule that about sixty percent of calcium filtered through the glomerulus is reabsorbed. The calcium carriage is done by claudins, an important components of the epithelial tight junctions found at tight junctions. Tight junctions are a surrounding cellular blockade that controls the flow of molecules in the intercellular space between the cells of an epithelium. The claudins perform selective transport and control the movement of solutes through the epithelium.

Some infrequent monogenic forms of stone formation can originally look a fine-print issue; lost detects of monogenetic reasons of nephrolithiasis might consequence to sub-optimal action, complications, and disappointment to screen at-risk family members [18,19,20]. Screening common pathogenic mutations by some novel high-throughput genomics-based strategies to assay GWAS SNPs, Sequencing by synthesis technology, Bead Array microarray technology, and is rapidly becoming an available diagnostic tool [15, 21]. In studies of hypercalciuric and hypocalciuric patients’ monogenic origins and infrequent alleles were not clearly recognized [22]. CLCN5 variants were a reasonable candidate for idiopathic hypercalciuria. However, those variants were found to be rare [23].

Several studies analyzed the associations of VDR gene expression with urolithiasis risk in different ethnic groups [24]. A meta-analysis by Imani D et al. indicated that although their study did not emphasize the relationship of FokI, TaqI, BsmI, and ApaI in the general sampled examination, but it proposes that ApaI and TaqI SNPs are linked to the bigger risk of urolithiasis in East-Asian and Caucasians populations [5]. It was indicated that urinary calcium excretion has increased in response to vitamin D (VitD) supplements, at least in some groups of kidney stone formers. It has been proposed that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements [25]. The VDR FokI polymorphism may be a good candidate for calcium oxalate stone disease marker. The epidemic of Randall plaque-associated renal stones in young patients can be the implication of altered vitamin D response [26].

Regarding CLDN, our data suggested the lower gene expression of CLDN can be the result of the promoter hypermethylation of CLDN. Similarly, Curryn JN and colleagues also described that a family with a rare missense variant in the CLDN gene has noticeable hypercalciuria, and kidney stone disease findings may indicate that CLDN can be a crucial regulator of calcium excretion and a potential target for therapies to prevent kidney stones [27]. Also, it was shown that single nucleotide polymorphisms of CLDN are significant in hypercalciuria and kidney stone formation [28]. The CLDN expression is downregulated in many pathologies, like cancer, inflammation, and fibrosis. The CLDN play an important role in energy-efficient ion and water transport in the proximal tubules of the kidneys and in the intestines. Notably, substantial studies highlighted a critical role for this protein as a modulator of critical cellular pathways related to stone diseases. Cell signaling pathways and molecular mechanism that are over activated in different conditions can change the claudin-2 expression, and a respectable association occurs concerning disease stage and claudin-2 overexpression. Additional, loss- and gain-of-function research presented that direct alterations in claudin-2 expression influence critical metabolic pathways in human cells. These properties seem to be intermediated by changes in critical signaling pathways [29].

The CaSR gene expression change commonly highlighted in the parathyroid glands and in renal tubules that control Parathyroid hormone (PTH) secretion. The kidneys are the main route for the excretion of salt and water and have an important role in the control of body fluid osmolality and Intracellular fluid volume (ICFV) and extracellular fluid volume (ECFV). The kidney controls electrolyte and water excretion, fix different tubular segments’ functions. In particular, CaSR decreases both passive and active calcium reabsorption in distal tubules, raises phosphate reabsorption in proximal tubules, and triggers proton and water excretion in collecting ducts. Therefore, it can be an important gene for causing calcium nephrolithiasis. Our data indicated a less critical role of Cas R epigenetic control in recurrent kidney stones formation. Some contradictory results showed an essential function of Cas R [30]. One possible explanation might be that Cas R cis’s gene expression is not regulated by epigenetic mechanisms like methylation.

Finally, we can say promoter hypermethylation of VRD and CLDN genes has an essential role in recurrent kidney stones formations.

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