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Podocyte-specific deletion of tubular sclerosis complex 2 promotes focal segmental glomerulosclerosis and progressive renal failure

岩田 和希子 横浜市立大学

2020.03.31

概要

Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podo- cyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2ǻpodocyte) devel- ops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2ǻpodocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2ǻpodocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)—unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2ǻpodocyte mice. Addi- tionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy speci- mens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.

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