Saroglitazar attenuates renal fibrosis induced by unilateral ureteral obstruction via inhibiting TGF-β/Smad signaling pathway
Saroglitazar attenuates renal fibrosis induced by unilateral ureteral obstruction via inhibiting TGF-β/Smad signaling pathway
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DOI：
10.1016/j.lfs.2020.117729
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发表时间：
2020-07-15
期刊：
影响因子：
6.1
通讯作者：
El-Kashef, Dalia H.
中科院分区：
文献类型：
--
作者：
Makled, Mirhan N.;El-Kashef, Dalia H.
阻塞性肾病是一种常见的临床病例，它导致慢性肾脏疾病并最终进展为终末期肾脏疾病。过氧化物酶体增殖物激活受体-α（PPAR-alpha）的激活可减少阻塞性nephropathy.Aims相关的肾小管间质纤维化和炎症反应：本研究旨在探讨沙格列扎、双重PPAR-alpha/gamma的潜在作用。方法：24只雄性Sprague道利大鼠随机分为假手术组、UUO模型组、沙格列扎组和沙格列扎组，每组6只。大鼠接受Saroglitazar（3 mg/kg/天）经口灌胃给药13天。在第14天，处死所有大鼠;收集血液和肾组织。关键发现：Saroglitazar可抑制UUO诱导的氧化应激，降低肾组织中MDA和一氧化氮的升高水平，升高GSH和SOD的水平。此外，Saroglitazar抑制UUO诱导的炎症;它降低了肾核因子κ B（NF-κ B）和白细胞介素-6（IL-6）的水平。此外，saroglitazar通过降低胶原、羟脯氨酸和基质金属蛋白酶-9（MMP-9）水平来抑制细胞外基质的积聚。Saroglitazar还降低了α平滑肌肌动蛋白（α-SMA）和肿瘤生长因子-β（TGF-β）的表达。这些影响是在平行减少母亲对decapentaplegic同系物3（smad 3）的表达和纤溶酶原激活物抑制剂-1（派-1）levels.Significance：总的来说，saroglitazar的保护作用可能是由于其抗氧化，抗炎和抗纤维化作用对UUO诱导的肾小管间质纤维化通过其调节作用对TGF-β 1/Smad 3信号通路。
Obstructive nephropathy is a common clinical case that causes chronic kidney disease and ultimately progresses to end-stage renal disease. The activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) reduces tubulointerstitial fibrosis and inflammation associated with obstructive nephropathy.Aims: This study was carried out to investigate the potential effect of saroglitazar, dual PPAR-alpha/gamma. agonist, in alleviating renal fibrosis induced by unilateralureteral obstruction (UUO).Main methods: Twenty-four male Sprague Dawley rats were haphazardly divided into four groups of six rats each, including sham operated group, vehicle-or saroglitazar-treated UUO and saroglitazar groups. Rats received oral gavage of saroglitazar (3 mg/kg/day) for 13 days. On day 14, all rats were sacrificed; blood and renal tissues were collected. Key findings: Saroglitazar inhibited UUO-induced oxidative stress; it decreased the elevated levels of MDA and nitric oxide and increased levels of GSH and SOD in renal tissue. Moreover, saroglitazar repressed UUO-induced inflammation; it decreased the renal levels of nuclear factor kappa B (NF-kappa B) and interleukin-6 (IL-6). Furthermore, saroglitazar inhibited the accumulation of extracellular matrix via decreasing collagen, hydroxylproline and matrix metalloproteinase-9 (MMP-9) levels. Saroglitazar also decreased the expression of both the alpha smooth muscle actin (alpha-SMA) and tumor growth factor-beta (TGF-beta). These effects were in parallel with reduction in mothers against decapentaplegic homolog 3 (smad3) expression and plasminogen activator inhibitor-1 (PAI-1) levels.Significance: Collectively, the protective impact of saroglitazar might be attributed to its antioxidant, anti-inflammatory and anti-fibrotic effects against UUO-induced tubulointerstitial fibrosis through its regulatory effect on TGF-beta 1/Smad3 signaling pathway.