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Inhibition of mitochondrial fission protects podocytes from albumin-induced cell damage in diabetic kidney disease.

TAGAYA Makoto KUME Shinji 00452235 0000-0001-6937-9715 YASUDA-YAMAHARA Mako 70731941 KUWAGATA Shogo 00791617 YAMAHARA Kosuke 50731915 TAKEDA Naoko 20737655 TANAKA Yuki CHIN-KANASAKI Masami 30402720 NAKAE Yuki 40638186 YOKOI Hideki 0000-0001-8343-9737 MUKOYAMA Masashi ISHIHARA Naotada NOMURA Masatoshi ARAKI Shin-ichi 80378455 0000-0002-2933-0316 MAEGAWA Hiroshi 00209363 0000-0002-4611-8149 滋賀医科大学

2022.02.21

概要

Aims:
Identifying the mechanisms that underlie progression from endothelial damage to podocyte damage, which leads to massive proteinuria, is an urgent issue that must be clarified to improve renal outcome in diabetic kidney disease (DKD). We aimed to examine the role of dynamin-related protein 1 (Drp1)-mediated regulation of mitochondrial fission in podocytes in the pathogenesis of massive proteinuria in DKD.

Methods:
Diabetes- or albuminuria-associated changes in mitochondrial morphology in podocytes were examined by electron microscopy. The effects of albumin and other diabetes-related stimuli, including high glucose (HG), on mitochondrial morphology were examined in cultured podocytes. The role of Drp1 in podocyte damage was examined using diabetic podocyte-specific Drp1-deficient mice treated with neuraminidase, which removes endothelial glycocalyx.

Results:
Neuraminidase-induced removal of glomerular endothelial glycocalyx in nondiabetic mice led to microalbuminuria without podocyte damage, accompanied by reduced Drp1 expression and mitochondrial elongation in podocytes. In contrast, streptozotocin-induced diabetes significantly exacerbated neuraminidase-induced podocyte damage and albuminuria, and was accompanied by increased Drp1 expression and enhanced mitochondrial fission in podocytes. Cell culture experiments showed that albumin stimulation decreased Drp1 expression and elongated mitochondria, although HG inhibited albumin-associated changes in mitochondrial dynamics, resulting in apoptosis. Podocyte-specific Drp1-deficiency in mice prevented diabetes-related exacerbation of podocyte damage and neuraminidase-induced development of albuminuria. Endothelial dysfunction-induced albumin exposure is cytotoxic to podocytes. Inhibition of mitochondrial fission in podocytes is a cytoprotective mechanism against albumin stimulation, which is impaired under diabetic condition. Inhibition of mitochondrial fission in podocytes may represent a new therapeutic strategy for massive proteinuria in DKD.

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