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

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.

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

“…Recently, it has been reported that megalin in proximal tubules is working as a novel endocytic receptor for renin and prorenin. In vitro experiments discovered that endocytosis of renin and pro-renin by megalin is accompanied with (P)RR by Sun et al [ 20 ] and others [ 21 , 22 ], suggesting limited roles of (P)RR for renin/prorenin binding in tubules. This evidence indirectly might be relevant to our findings that (P)RR and renin/prorenin are tenously related physiologically.…”

Cardiovascular aspects of the (pro)renin receptor: Function and significance

“…Secondly, the binding of prorenin to PRR also induces intracellular signaling such as the p38 MAPK/HSP27 pathway in cardiomyocytes independently of IGF2R and AngII, 51 resulting in alterations in actin filament dynamics, and thereby the severe cardiac hypertrophy 52 . Thus, we propose that PRR‐mediated internalization of prorenin may be apart from megalin and IGF2R, but megalin‐mediated uptake of prorenin requires PRR 4–6 . In addition, AT1 receptor‐mediated endocytosis of AngII from blood may also contribute to the accumulation of AngII that plays an important physiological role in cardiomyocytes 53…”

“…52 Thus, we propose that PRR-mediated internalization of prorenin may be apart from megalin and IGF2R, but megalin-mediated uptake of prorenin requires PRR. [4][5][6] In addition, AT1 receptor-mediated endocytosis of AngII from blood may also contribute to the accumulation of AngII that plays an important physiological role in cardiomyocytes. 53…”

“…6,49,50 Of note, it has been reported that PRR facilitated receptor-mediated endocytosis possibly by modulating H + -ATPases. 6 Secondly, the binding of prorenin to PRR also induces intracellular signaling such as the p38 MAPK/HSP27 pathway in cardiomyocytes independently of IGF2R and AngII, 51 resulting in alterations in actin filament dynamics, and thereby the severe cardiac hypertrophy. 52 Thus, we propose that PRR-mediated internalization of prorenin may be apart from megalin and IGF2R, but megalin-mediated uptake of prorenin requires PRR.…”

“Nomen not est omen”: the (pro)renin receptor and receptor-mediated endocytosis in the proximal tubule—a new (pro)renin-independent role forATP6ap2

“…In the present study, Figueiredo et al [2] investigated the role of ATP6ap2 in receptor-mediated endocytosis in the proximal tubule. Using two different models, the authors showed that depletion of ATP6ap2 resulted in proteinuria and increased urinary excretion of three megalin ligands.…”