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bioRxiv · 10.1101/2020.12.04.412635

Loss of phosphatidylserine flippase β-subunit Tmem30a in podocytes leads to albuminuria and glomerulosclerosis

Zhu, X.·Liu, W.·Peng, L.·Tian, W.·Li, Y.·Zhang, P.·Sun, K.·Yang, Y.·Li, X.·Li, G.
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Abstract

Phosphatidylserine (PS) is asymmetrically concentrated in the cytoplasmic leaflet of eukaryotic cell plasma membranes. This asymmetry is regulated by a group of P4 ATPases (named PS flippases) and its {beta}-subunit TMEM30A. The disruption of PS flippase leads to severe human diseases. Tmem30a is essential in the mouse retina, cerebellum and liver. However, the role of Tmem30a in the kidney, where it is highly expressed, remains unclear. Podocytes in the glomerulus form a branched interdigitating filtration barrier that can prevent the traversing of large cellular elements and macromolecules from the blood into the urinary space. Damage to podocytes can disrupt the filtration barrier and lead to proteinuria and podocytopathy, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and diabetic nephropathy. To investigate the role of Tmem30a in the kidney, we generated a podocyte-specific Tmem30a knockout (cKO) mouse model using the NPHS2-Cre line. Tmem30a KO mice displayed albuminuria, podocyte degeneration, mesangial cell proliferation with prominent extracellular matrix accumulation and eventual progression to focal segmental glomerulosclerosis (FSGS). Reduced TMEM30A expression was observed in patients with minimal change disease and membranous nephropathy, highlighting the clinical importance of TMEM30A in podocytopathy. Our data demonstrate a critical role of Tmem30a in maintaining podocyte survival and glomerular filtration barrier integrity. Understanding the dynamic regulation of the PS distribution in the glomerulus provides a unique perspective to pinpoint the mechanism of podocyte damage and potential therapeutic targets.

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Zhu, X., Liu, W., Peng, L., Tian, W., Li, Y., Zhang, P., Sun, K., Yang, Y., Li, X., Li, G.. 2020-12-05. Loss of phosphatidylserine flippase β-subunit Tmem30a in podocytes leads to albuminuria and glomerulosclerosis. https://doi.org/10.1101/2020.12.04.412635

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