Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy.
Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy.
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DOI：
10.1016/j.redox.2022.102260
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发表时间：
2022-04
期刊：
影响因子：
11.4
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Liu L;Bai F;Song H;Xiao R;Wang Y;Yang H;Ren X;Li S;Gao L;Ma C;Yang X;Liang X
肾小管上皮细胞(RTECs)是最富含线粒体的细胞类型之一，因此容易受到线粒体失调的影响，线粒体失调被定义为糖尿病肾病(DN)肾小管损害的关键事件。然而，潜在的机制在很大程度上仍不清楚。在此，我们研究了肿瘤坏死因子α诱导蛋白8样蛋白1(TNFAIP8L1/TIPE1)在高糖(HG)诱导的RTECs线粒体功能障碍和糖尿病肾病进展中的作用和机制。在糖尿病肾病患者和链脲佐菌素(STZ)诱导的糖尿病肾病小鼠的RTECs中，TIPE1的表达显著上调。RTECs中Tipe1的条件性基因敲除显著降低了STZ诱导的小鼠的尿蛋白肌酐比、肾小管损伤、上皮-间质转化和间质纤维化。RNA测序显示，在RTEC特异性Tipe1基因敲除小鼠的肾组织中，柠檬酸循环相关基因正向富含。Tipe1缺乏上调了RTECs的ATP水平、线粒体膜电位和呼吸速率，但下调了线粒体ROS水平。此外，Tipe1消融导致RTECs有丝分裂能力增强，表明LC3II、PINK1和Parkin表达增加，但线粒体p62表达减少。从机理上讲，质谱学筛选和免疫共沉淀分析表明，TIPE1与关键的有丝分裂受体--禁止素2(PHB2)相互作用。有趣的是，TIPE1促进了PHB2的泛素化和蛋白酶体降解。随后，PHB2基因敲除几乎取消了Tipe1缺失对HG诱导的肾小管细胞有丝分裂和损伤的改善作用。因此，TIPE1破坏了RTECs中线粒体的动态平衡，并通过在HG条件下破坏PHB2的稳定而促进了肾小管损伤。因此，TIPE1可能成为预防糖尿病肾病进展的潜在治疗靶点。TIPE1在糖尿病肾病的RTEC中高表达。TIPE1加重糖尿病肾脏损伤和纤维化。TIPE1通过抑制有丝分裂来破坏RTECs线粒体的动态平衡。TIPE1与PHB2蛋白酶体相互作用并促进其降解。
Renal tubular epithelial cells (RTECs) are one of the most mitochondria-rich cell types, and are thus vulnerable to mitochondrial dysregulation, which is defined as a pivotal event in tubular damage in diabetic nephropathy (DN). However, the underlying mechanisms remain largely unknown. Here, we investigated the role and mechanisms of tumor necrosis factor alpha-induced protein 8-like 1 (TNFAIP8L1/TIPE1) in high glucose (HG)-induced mitochondrial dysfunction in RTECs and DN progression. TIPE1 expression was predominantly upregulated in RTECs in patients with DN and mice with streptozotocin (STZ)-induced DN. Conditional knockout of Tipe1 in RTECs significantly decreased the urine protein creatinine ratio, renal tubular damage, epithelial-mesenchymal transition, and interstitial fibrosis in STZ-induced mice. RNA sequencing revealed that citrate cycle-related genes were positively enriched in the renal tissues of RTEC-specific Tipe1 knockout mice. Tipe1 deficiency upregulated ATP levels, mitochondrial membrane potential, and respiration rate, but downregulated mitochondrial ROS levels in RTECs. Furthermore, Tipe1 ablation led to enhanced mitophagy in RTECs, indicative of increased LC3II, PINK1, and Parkin expression, but decreased p62 expression in mitochondria. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed the interaction of TIPE1 with prohibitin 2 (PHB2), a crucial mitophagy receptor. Intriguingly, TIPE1 promoted the ubiquitination and proteasomal degradation of PHB2. Subsequently, PHB2 knockdown almost abrogated the improvement of Tipe1 loss on HG-induced tubular cell mitophagy and damage. Thus, TIPE1 disrupts mitochondrial homeostasis in RTECs and promotes tubular damage by destabilizing PHB2 under HG conditions. Hence, TIPE1 may act as a potential therapeutic target to prevent DN progression. TIPE1 is highly expressed in RTECs of DN. TIPE1 aggravates diabetic renal injury and fibrosis. TIPE1 disrupts the mitochondria homeostasis of RTECs by inhibiting mitophagy. TIPE1 interacts with and promotes the proteasomal degradation of PHB2.
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