Febuxostat attenuates ER stress mediated kidney injury in a rat model of hyperuricemic nephropathy

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.

Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

“…This process is mediated by caspase-12, an ER-specific caspase, via activation of the caspase-9/caspase-3 cascade 20 . A recent study has also shed light on the profibrotic role of a novel ER-associated protein, RTN1A 21 , 25 . RTN1A is related to prolonged ER stress and apoptosis of TECs 25 .…”

“…A recent study has also shed light on the profibrotic role of a novel ER-associated protein, RTN1A 21 , 25 . RTN1A is related to prolonged ER stress and apoptosis of TECs 25 . Specific knockout of RTN1A in TECs could downregulate ER stress signaling and ameliorate ER stress-associated apoptosis 21 .Please define PERK–eIF2–ATF4, IRE1-XBP1, ATF6, MAPK/ERK at its first mention in text.PERK–eIF2–ATF4 stands for PRKR-like endoplasmic reticulum kinase-eukaryotic translation initiation factor 2-activating transcription factor 4IRE1–XBP1 stands for inositol-requiring enzyme 1-X-Box binding protein 1ATF6 stands for activating transcription factor 6MAPK/ERK stands for mitogen-activated protein kinase…”

Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury

“…ER stress is closely associated with renal fibrosis [ 102 , 103 ]. Recently, He et al [ 104 ] found that a marker of ER stress (RTN1A) was markedly upregulated in hyperuricemic nephropathy; however, febuxostat suppressed ER stress, thereby improving kidney injury and interstitial fibrosis [ 105 ]. Thus, MMPs and ER stress may be additional hallmarks and therapeutic targets for hyperuricemia-induced renal interstitial fibrosis.…”

Comparative Efficacy of the Course Injection Therapy with Iniectran or in Combination with Fermathron in Patients with Osteoarthritis of the Ankle Joints on the Background of Genytron Basic Application

“…Он повышал практически до нормы уровень креатинина и мочевины в крови, а также лактатдегидрогеназы и ФНО-альфа [26]. В другом исследовании применение фебуксостата привело к заметному снижению тубулоинтерстициального повреждения и фиброза в модели гиперурикемической нефропатии у крыс [27]. Полученные результаты стали основанием для более пристального анализа антиоксидантных, противовоспалительных и цитопротективных свойств препарата.…”