Institute of Physiology, College of Life Sciences, Shaanxi Normal University, Xi'an, China; School of Medicine, Northwest University, Xi'an, Shaanxi 710069, China.
The Affiliated Xi'an People's Hospital (Xi'an Fourth Hospital) of Northwest University, Xi'an, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166701. doi: 10.1016/j.bbadis.2023.166701. Epub 2023 Mar 28.
Hypoxia-regulated proximal tubular epithelial cells (PTCs) G2/M phase arrest/delay was involved in production of renal tubulointerstitial fibrosis (TIF). TIF is a common pathological manifestation of progression in patients with chronic kidney disease (CKD), and is often accompanied by lipid accumulation in renal tubules. However, cause-effect relationship between hypoxia-inducible lipid droplet-associated protein (Hilpda), lipid accumulation, G2/M phase arrest/delay and TIF remains unclear. Here we found that overexpression of Hilpda downregulated adipose triglyceride lipase (ATGL) promoted triglyceride overload in the form of lipid accumulation, leading to defective fatty acid β-oxidation (FAO), ATP depletion in a human PTC cell line (HK-2) under hypoxia and in mice kidney tissue treated with unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Hilpda-induced lipid accumulation caused mitochondrial dysfunction, enhanced expression of profibrogenic factors TGF-β1, α-SMA and Collagen I elevation, and reduced expression of G2/M phase-associated gene CDK1, as well as increased CyclinB1/D1 ratio, resulted in G2/M phase arrest/delay and profibrogenic phenotypes. Hilpda deficiency in HK-2 cell and kidney of mice with UUO had sustained expression of ATGL and CDK1 and reduced expression of TGF-β1, Collagen I and CyclinB1/D1 ratio, resulting in the amelioration of lipid accumulation and G2/M arrest/delay and subsequent TIF. Expression of Hilpda correlated with lipid accumulation, was positively associated with tubulointerstitial fibrosis in tissue samples from patients with CKD. Our findings suggest that Hilpda deranges fatty acid metabolism in PTCs, which leads to G2/M phase arrest/delay and upregulation of profibrogenic factors, and consequently promote TIF which possibly underlie pathogenesis of CKD.
缺氧诱导的近端肾小管上皮细胞（PTC）G2/M 期阻滞/延迟参与了肾小管间质纤维化（TIF）的发生。TIF 是慢性肾脏病（CKD）患者进展的常见病理表现，常伴有肾小管内脂质堆积。然而，缺氧诱导的脂滴相关蛋白（Hilpda）、脂质堆积、G2/M 期阻滞/延迟与 TIF 之间的因果关系尚不清楚。我们发现，Hilpda 的过表达下调脂肪甘油三酯脂肪酶（ATGL），促进以脂质堆积为形式的甘油三酯过载，导致脂肪酸β氧化（FAO）缺陷、ATP 耗竭，在缺氧状态下的人 PTC 细胞系（HK-2）和单侧输尿管梗阻（UUO）及单侧缺血再灌注损伤（UIRI）处理的小鼠肾脏组织中均如此。Hilpda 诱导的脂质堆积导致线粒体功能障碍，增强了致纤维化因子 TGF-β1、α-SMA 和 Collagen I 的表达，降低了 G2/M 期相关基因 CDK1 的表达，同时增加了 CyclinB1/D1 比值，导致 G2/M 期阻滞/延迟和致纤维化表型。在 UUO 小鼠的 HK-2 细胞和肾脏中 Hilpda 缺失可维持 ATGL 和 CDK1 的表达，降低 TGF-β1、Collagen I 和 CyclinB1/D1 比值，从而改善脂质堆积和 G2/M 期阻滞/延迟，随后减轻 TIF。Hilpda 的表达与脂质堆积相关，与 CKD 患者组织样本中的肾小管间质纤维化呈正相关。我们的研究结果表明，Hilpda 扰乱了 PTC 中的脂肪酸代谢，导致 G2/M 期阻滞/延迟和致纤维化因子的上调，进而促进 TIF，这可能是 CKD 发病机制的基础。
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