Endocrine Abstracts

Backgrounds: Podocytes are highly specialized postmitotic kidney cells that contribute to maintaining the filtration barrier and normal structure of glomerular capillaries. The (pro)renin receptor (PRR), as ATP6AP2, is an accessory subunit of the vacuolar H+-ATPase (V-ATPase), implying more fundamental, developmental functions for the PRR in addition to its role in activating the local renin-angiotensin system.

Results: Podocyte-specific conditional (P)RR knockout (CKO) in mice resulted in lethal kidney failure with severe proteinuria, with CKO mice dying within 4 weeks of birth. The histologic examination revealed that as early as on postnatal day 7, the podocytes of CKO mice exhibited foot process effacement and numerous autophagic vacuoles, along with focal and segmental mesangium cell proliferation. This was confirmed by reduction and altered localization in nephrin and podocin expression, as well as increased expressions of RAB7, lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1 light chain 3 (LC3) in CKO podocytes. Notably, over the course of development in CKO mice, nephrin expression became discontinuous and was seen mainly in the cytosol of podocytes. The number of cells positive for WT1, a nuclear marker for podocytes, was significantly fewer in glomeruli from CKO mice on postnatal day 20, implying increased podocyte cell death or detachment from basement membrane. In vitro analysis revealed that the treatment with the siRNA knocking down of PRR/ATP6AP2 reduced the protein expression of nephrin in the human cultured podocytes despite the up-regulation of NPHS1 mRNA expression. Also, the inhibition of PRR expression selectively suppressed expression of VO subunit c of the V-ATPase in podocytes, resulting in deacidification of the intracellular vesicles and increased autophagic vacuoles.

Conclusions: A deficiency of the PRR in podocytes resulted in impaired expression of slit diaphragm proteins and increase in the late endosomes, lysosomes, and autophagosomes, due to V-ATPase dysfunction.

Electron microscopic examination of kidneys from conditional (pro)renin receptor-knockout (CKO) mice on postnatal day 14. Kidneys from CKO mice were found to contain prominently enlarged podocytes with extensive foot process effacement and actin filament aggregation. Numerous electron-dense autophagic vacuoles containing partially digested cellular components were observed in the cytoplasm of these podocytes. Mesangial matrix expansion was also noted in CKO glomeruli.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.