KCA3.1 REGULATES MITOPHAGY IN DIABETIC KIDNEY DISEASE

C HUANG1, H YI1, Y SHI1, Q CAO1, X-M CHEN1, C POLLOCK1

1Kolling Institute, University Of Sydney, Sydney, Australia

Aim: To identify the role of KCa3.1 in mitophagy in diabetic kidney disease.

Background: Mitophagy, the selective degradation of mitochondria by autophagy, has been shown to be involved in the pathogenesis of diabetic kidney disease. It has been demonstrated that blockade of KCa3.1, a potassium channel, ameliorates diabetic renal fibrosis and KCa3.1 activation contributes to dysfunctional tubular autophagy in diabetic nephropathy through PI3K/Akt/mTOR signaling pathways. However, the mechanistic link between KCa3.1 and mitophagy in diabetic kidney disease remains unknown.

Methods: In vitro human proximal tubular cells (HK2 cells) transfected with scrambled siRNA or KCa3.1 siRNA were exposed to TGF-β1 for 48h. Mitochondrial ATP production and mitochondrial ROS (mtROS) production were assessed. In vivo, diabetes was induced in KCa3.1+/+ and KCa3.1-/- mice by streptozotocin injection. The mitophagy markers (LC3 and P62) and mitophagy related protein, BCL2 interacting protein 3 (BNIP3) were examined in HK2 cells and mice kidneys.

Results: The in vitro results showed that TGF-β1 significantly inhibited mitochondrial ATP production rate, compared to the controls, which were significantly reversed by KCa3.1 siRNA in HK2 cells. KCa3.1 gene silencing inhibited TGF-β1-induced significant increase in MitoSOX Red fluorescence in HK2 cells. TGF-β1 significantly increased the expression of the mitophagy markers LC3, P62 and mitophagy related protein BNIP3 in HK2 cells, which were attenuated by KCa3.1 gene silencing. Consistently, the in vivo results showed significantly increased LC3, P62 and BNIP3 expression in diabetic KCa3.1 +/+ mice, which were significantly reduced in diabetic KCa3.1-/- mice.

Conclusions: KCa3.1 inhibition ameliorates diabetic kidney disease through modulation of mitophagy.


Biography:

Dr Huang is a research fellow in the renal Research Group at Kolling Institute, Sydney Medical School, University of Sydney. She has expertise in diabetic kidney disease, animal models of diabetic nephropathy and kidney fibrosis. Her research investigates the novel targets for diabetic kidney disease and the underling mechanisms including inflammation, fibrosis, fibroblast activation and autophagy.

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