Mechanistic insights into hyperuricemia-associated renal abnormalities with special emphasis on epithelial-to-mesenchymal transition: Pathologic implications and putative pharmacologic targets

Though the pathogenesis of hyperuricemia-induced renal complications is not precisely known, hyperuricemia has been recognized as an independent risk factor for renal disease. While the clinical implication of hyperuricemia in renal disease has been a contemporary topic of debate, growing body of bench and clinical evidences certainly suggest a causative role of high uric acid in renal abnormalities by implicating diverse pathologic and molecular mechanisms. Urate crystals after having deposited in the kidney could cause hyperuricemia nephropathy leading to glomerular hypertrophy and tubulointerstitial fibrosis, while high serum uric acid might predict progressive renal damage and dysfunction. Hyperuricemia could be associated with manifestation of tubular injury and macrophage infiltration as well as an increased expression of inflammatory mediators. This review sheds light on the mechanistic aspects pertaining to hyperuricemia-associated renal abnormalities. Besides, the renal detrimental actions of high uric acid possibly mediated through its potential role on oxidative stress, renal inflammation, endothelial dysfunction, glycocalyx shedding, endothelial-to-mesenchymal transition and more specifically on the renal epithelial-to-mesenchymal transition have been addressed. Moreover, this review discusses a number of potential targets such as endothelin-1, TLR4/NF-kB, PI3K/p-Akt, Wnt5a/Ror2, NLRP3 inflammasome, NADPH oxidase, ERK1/2, enhancer of zeste homolog 2, serum response factor and Smad3/TGF-β signalling pathways, among others, implicated in hyperuricemia-associated renal abnormalities. This review finally apprises a number of bench and clinical studies which supporting a notion that the pharmacologic reduction of high uric acid might have a therapeutic value in the management of renal abnormalities, with an emphasis on febuxostat and its renal pleiotropic actions.