Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes

被引:38
作者
Audzeyenka, Irena [1 ,2 ]
Rachubik, Patrycja [1 ]
Typiak, Marlena [1 ]
Kulesza, Tomasz [1 ]
Topolewska, Anna [2 ]
Rogacka, Dorota [1 ,2 ]
Angielski, Stefan [1 ]
Saleem, Moin A. [3 ]
Piwkowska, Agnieszka [1 ,2 ]
机构
[1] Polish Acad Sci, Mossakowski Med Res Inst, Lab Mol & Cellular Nephrol, Wita Stwosza St, PL-80308 Gdansk, Poland
[2] Univ Gdansk, Fac Chem, Wita Stwosza St, PL-80308 Gdansk, Poland
[3] Univ Bristol, Bristol Renal, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England
关键词
Diabetic nephropathy; Podocytes; Bioenergetics; Mitochondrial dynamics; Mitophagy; HIGH GLUCOSE; INSULIN-RESISTANCE; DNA CONTENT; METABOLISM; INJURY; DYSFUNCTION; DYNAMICS; GROWTH; NUCLEOTIDES; APOPTOSIS;
D O I
10.1016/j.yexcr.2021.112758
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Podocytes constitute the outer layer of the renal glomerular filtration barrier. Their energy requirements strongly depend on efficient oxidative respiration, which is tightly connected with mitochondrial dynamics. We hypothesized that hyperglycemia modulates energy metabolism in glomeruli and podocytes and contributes to the development of diabetic kidney disease. We found that oxygen consumption rates were severely reduced in glomeruli from diabetic rats and in human podocytes that were cultured in high glucose concentration (30 mM; HG). In these models, all of the mitochondrial respiratory parameters, including basal and maximal respiration, ATP production, and spare respiratory capacity, were significantly decreased. Podocytes that were treated with HG showed a fragmented mitochondrial network, together with a decrease in expression of the mitochondrial fusion markers MEN1, MFN2, and OPA1, and an increase in the activity of the fission marker DRP1. We showed that markers of mitochondrial biogenesis, such as PGC-1 alpha and TFAM, decreased in HG-treated podocytes. Moreover, PINK1/parkin-dependent mitophagy was inhibited in these cells. These results provide evidence that hyperglycemia impairs mitochondrial dynamics and turnover, which may underlie the remarkable deterioration of mitochondrial respiration parameters in glomeruli and podocytes.
引用
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页数:11
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