Podocytes are component cells of the glomerular filtration barrier, and their loss by apoptosis is the main cause of proteinuria that leads to diabetic nephropathy (DN). Therefore, insights into podocyte apoptosis mechanism would allow a better understanding of DN pathogenesis and thus help develop adequate therapeutic strategies. Here, we investigated the molecular mechanism of palmitic acid-inhibited cell death in mouse podocytes, and found that palmitic acid increased cell death in a dose- and time-dependent manner. Palmitic acid induces apoptosis in podocytes through upregulation of cytosolic and mitochondrial Ca2+, mitochondrial membrane potential (MMP), cytochrome c release, and depletion of endoplasmic reticulum (ER) Ca2+. The intracellular calcium chelator, 1,2-bis (2-aminophenoxy) ethane-N,N,N, N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM), partially prevented this upregulation whereas 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-triphosphate receptor (IP3R) inhibitor; dantrolene, a ryanodine receptor (RyR) inhibitor; and 4,4'-diisothiocyanatostibene-2,2'-disulfonic acid (DIDS), an anion exchange inhibitor, had no effect. Interestingly, ruthenium red and Ru360, both inhibitors of the mitochondrial Ca2+ uniporter (MCU), blocked palmitic acid-induced mitochondrial Ca2+ elevation, cytochrome c release from mitochondria to cytosol, and apoptosis. siRNA to MCU markedly reduced palmitic acid-induced apoptosis. These data indicate that Ca2+ uptake via mitochondrial uniporter contributes to palmitic acid-induced apoptosis in mouse podocytes. (c) 2017 Wiley Periodicals, Inc.
[1]Shanghai Univ Tradit Chinese Med, Intervent Canc Inst Chinese Integrat Med, Putuo Hosp, Shanghai 200062, Peoples R China.
[2]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Lab Renal Dis, Shanghai 200062, Peoples R China.
[3]Shanghai Gen Hosp, Dept Clin Pharm, Shanghai 201620, Peoples R China.
[4]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Nephrol, 164 Lanxi Rd, Shanghai 200062, Peoples R China.
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