Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress

被引：179

作者：

Xu, S. ^{[1
,2
]}

Nam, S. M. ^{[1
,2
,3
]}

Kim, J-H ^{[1
,2
]}

Das, R. ^{[1
,2
]}

Choi, S-K ^{[1
,2
]}

Nguyen, T. T. ^{[1
,2
]}

Quan, X. ^{[1
,2
]}

Choi, S. J. ^{[4
]}

Chung, C. H. ^{[5
]}

Lee, E. Y. ^{[6
]}

Lee, I-K ^{[7
]}

Wiederkehr, A. ^{[8
]}

Wollheim, C. B. ^{[9
]}

Cha, S-K ^{[1
,2
]}

Park, K-S ^{[1
,2
]}

机构：

[1] Yonsei Univ, Wonju Coll Med, Dept Physiol, Wonju 220701, Gangwon Do, South Korea

[2] Yonsei Univ, Wonju Coll Med, Inst Lifestyle Med, Wonju 220701, Gangwon Do, South Korea

[3] Daejeon Sun Hosp, Dept Internal Med, Daejeon, South Korea

[4] Yonsei Univ, Wonju Coll Med, Dept Microbiol, Wonju 220701, Gangwon Do, South Korea

[5] Yonsei Univ, Wonju Coll Med, Dept Internal Med, Wonju 220701, Gangwon Do, South Korea

[6] Soonchunhyang Univ, Cheonan Hosp, Dept Internal Med, Cheonan, South Korea

[7] Kyungpook Natl Univ Hosp, Dept Internal Med, Daegu, South Korea

[8] Nestle Inst Hlth Sci, Lausanne, Switzerland

[9] Univ Geneva, Dept Cell Physiol & Metab, Geneva, Switzerland

来源：

CELL DEATH & DISEASE | 2015年 / 6卷

基金：

新加坡国家研究基金会;

关键词：

ENDOPLASMIC-RETICULUM STRESS; PANCREATIC BETA-CELLS; SKELETAL-MUSCLE CELLS; FATTY-ACIDS; INSULIN-RESISTANCE; ACTIN DYNAMICS; TRPC6; CHANNELS; CA2+; DYSFUNCTION; ACTIVATION;

D O I：

10.1038/cddis.2015.331

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca2+ increase due to depletion of luminal ER Ca2+. Palmitate-induced ER Ca2+ depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca2+ pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca2+ depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate-induced ER Ca2+ loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca2+ depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA leads to mitochondrial dysfunction and ER Ca2+ depletion through FAT/CD36 and PLC signaling, possibly contributing to podocyte injury.

引用

页码：e1976 / e1976

页数：13

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