대한신장학회

논문분류	춘계학술대회 초록집
제목	Angiotensin II-mediated MYH9 down-regulation causes structural and functional podocyte injury in diabetic kidney disease
저자	Jeong suk KANG1, Seung joo LEE1, ji-hye LEE2, Ji-hee KIM4, Ah reum JOENG1, Seung seob SON1, Seung-kuy CHA4, *Choon hee CHUNG3
출판정보	2017; 2017(1):
키워드	당뇨병성 신손상 (Diabetic renal injury), 뇨여과장벽 (Urinary filtration barrier), 단백뇨 (proteinuria), MYH9
초록	Objectives : Podocytes serve as an important constituent of the glomerular filtration barrier, and their injury and loss have been suggested to play crucial roles in the pathogenesis of diabetic nephropathy. MYH9 is a podocyteexpressed gene encoding a non-muscle myosin IIA heavy chain and is associated with glomerular pathophysiology. The mechanisms responsible for MYH9-related glomerular diseases are poorly understood. This study investigated the mechanism of podocyte dysfunction induced by MYH9 deficiency in diabetic kidney injury. Methods : MYH9 expression was examined in the kidneys from proteinuric diabetic patients and animal models. In vitro, we knocked down MYH9 gene by target siRNA in podocytes. MYH9 siRNA-transfected podocytes were treated with angiotensin II (Ang II), a key mediator of various kidney injury, for 72h. Podocyte cytoskeleton, migration, adhesion, and permeability were assessed. Gene and protein expression were examined by real-time RT-PCR, western blot and immunofluorescence. Results : MYH9 expression was decreased in glomeruli from diabetic humans and animals compared with nondiabetic glomeruli. Podocytes treated with angiotensin II (Ang II), which is up-regulated in diabetic glomeruli, decreased the expression of MYH9 in vitro. siRNA-mediated MYH9 knockdown in podocytes resulted in morphological changes due to reorganization of actin cytoskeleton, reduced cell adhesion, increased cell migration, up-regulated NOX4 expression, and increased reactive oxygen species (ROS) generation. Stimulating MYH9-deleted podocytes with Ang II exacerbated these changes. The Ang II receptor blocker, losartan, and the ROS scavenger, N-acetyl Lcysteine, attenuated MYH9 depletion-induced disruption of actin cytoskeleton, which leads to the prevention of increased albumin permeability. Ang II mediated overexpression of TRPC6 reduced MYH9 expression. Conclusions : The data provide the first evidence that Ang II-mediated MYH9 depletion in diabetic nephropathy may increase filtration barrier permeability by the structural and functional podocyte injury through NOX4-mediated ROS generation and TRPC6-mediated Ca2+ influx. These findings reveal a novel function of MYH9 in maintaining the integrity of urinary filtration barrier. MYH9 may be a potential target for the treatment of diabetic nephropathy. This research was supported by Basic Science Research Program throuh the National Research Foundation of Korea(NRF) funded by the Ministry of Education (2015R1A6A1A03032522).
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