Abstract
Hyperuricemia contributes to kidney tubular injury and kidney fibrosis. However, the underlying mechanism remains unclear. Here we examined the role of RTN1A, a novel endoplasmic reticulum (ER)-associated protein and ER stress in hyperuricemic nephropathy. We first found the expression of RTN1A and ER stress markers was significantly increased in kidney biopsies of hyperuricemia patients with kidney injury. In a rat model of hyperuricemic nephropathy (HN) established by oral administration of a mixture of adenine and potassium oxonate, increased expression of RTN1A and ER stress was shown in tubular and interstitial compartment of rat kidneys. Treatment of Febuxostat, a new selective inhibitor of xanthine oxidase (XO), not only attenuated renal tubular injury and tubulointerstitial fibrosis, but also reduced uric acid crystals deposition in HN rat kidneys. In vitro, Febuxostat also reduced ER stress and apoptosis in uric acid treated tubular epithelial cells. Our data suggest that RTN1A and ER stress mediate tubular cell injury and kidney fibrosis in HN. Urate-lowering therapy (ULT) with Febuxostat attenuates uric-acid induced ER stress in renal tubular cells and the progression of HN.
Highlights
Increasing evidence indicates that hyperuricemia is an independent risk factor for the onset and progression of chronic kidney disease (CKD)[1]
It is known that hyperuricemia is associated with upregulation of serum xanthine oxidase (XOD) activity, we found that the activity of serum XOD was markedly increased in hyperuricemic rats, which was reversed by Febuxostat treatment (Figure 5C), suggesting that Febuxostat contributes to the regulation of uric transporter and suppression of the XOD activity in hyperuricemic rats
In the current study we examined whether Febuxostat had renal protective effects in hyperuricemic nephropathy (HN) rat kidneys
Summary
Increasing evidence indicates that hyperuricemia is an independent risk factor for the onset and progression of chronic kidney disease (CKD)[1]. Studies showed that endothelial dysfunction, oxidative stress, inflammation and the activation of renin-angiotensin system may be involved in the hyperuricemia induced kidney injury [3,4,5,6,7]. The exact mechanism of hyperuricemic nephropathy (HN) and how hyperuricemia contributes to the progression of HN remains largely unknown. Quite a few randomized multi-central trials have confirmed a potent role of Febuxostat as urate-lowering therapy (ULT) in hyperuricemia induced gout [11, 12]. Recent studies suggested that lowering SUA levels by Febuxostat might contribute to cardiovascular and renal benefits [13]. The mechanism of this protective effect is largely unknown
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