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

Figueiredo, M.; Daryadel, A.; Sihn, G.; Müller, D.N.; Popova, E.; Rouselle, A.; Nguyen, G.; Bader, M.; Wagner, C.A.

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., Daryadel, A., Sihn, G., Müller, D.N., Popova, E., Rouselle, A., Nguyen, G., 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
ISSN:	0031-6768
Publisher:	Springer
Volume:	473
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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