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The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule

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Item Type:Article
Title:The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule
Creators Name:Figueiredo, M. and Daryadel, A. and Sihn, G. and Müller, D.N. and Popova, E. and Rouselle, A. and Nguyen, G. and Bader, M. and Wagner, C.A.
Abstract:The ATP6ap2 (Pro)renin receptor protein associates with H(+)-ATPases which regulate organellar, cellular, and systemic acid-base homeostasis. In the kidney, ATP6ap2 colocalizes with H(+)-ATPases in various cell types including the cells of the proximal tubule. There, H(+)-ATPases are involved in receptor-mediated endocytosis of low molecular weight proteins via the megalin/cubilin receptors. To study ATP6ap2 function in the proximal tubule, we used an inducible shRNA Atp6ap2 knockdown rat model (Kd) and an inducible kidney-specific Atp6ap2 knockout mouse model. Both animal lines showed higher proteinuria with elevated albumin, vitamin D binding protein, and procathepsin B in urine. Endocytosis of an injected fluid-phase marker (FITC- dextran, 10 kDa) was normal whereas processing of recombinant transferrin, a marker for receptor-mediated endocytosis, to lysosomes was delayed. While megalin and cubilin expression was unchanged, abundance of several subunits of the H(+)-ATPase involved in receptor-mediated endocytosis was reduced. Lysosomal integrity and H(+)-ATPase function are associated with mTOR signaling. In ATP6ap2, KO mice mTOR and phospho-mTOR appeared normal but increased abundance of the LC3-B subunit of the autophagosome was observed suggesting a more generalized impairment of lysosomal function in the absence of ATP6ap2. Hence, our data suggests a role for ATP6ap2 for proximal tubule function in the kidney with a defect in receptor-mediated endocytosis in mice and rats.
Keywords:Proximal Tubule, Low Molecular Weight Proteins, Lysosome, H(+)-ATPase, Endocytosis, Animals, Rats, Mice
Source:Pflugers Archiv
Page Range:1229-1246
Date:August 2021
Official Publication:https://doi.org/10.1007/s00424-021-02598-z
PubMed:View item in PubMed

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