Journal
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Volume 473, Issue 8, Pages 1229-1246Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00424-021-02598-z
Keywords
Proximal tubule; Low molecular weight proteins; Lysosome; H+-ATPase; Endocytosis
Categories
Funding
- Universitat Zurich
- Swiss National Science Foundation [31003A_138143, 31003A_155959]
- German Research Foundation (DFG) [SFB1365]
- Swiss National Science Foundation (SNF) [31003A_138143, 31003A_155959] Funding Source: Swiss National Science Foundation (SNF)
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The ATP6ap2 (Pro)renin receptor protein plays a role in proximal tubule function in the kidney, with knockout leading to increased proteinuria and impairment of receptor-mediated endocytosis.KO mice exhibited normal mTOR signaling but showed impairment of lysosomal function, suggesting a broader role for ATP6ap2 beyond the regulation of endocytosis.
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.
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