Prorenin Receptor Is Essential for Podocyte Autophagy and Survival

Abstract

The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H ϩ -ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.

A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells

“…This could also in part explain the decreased insulin secretion in cells with ATP6ap2 knocked down. ATP6ap2 has been shown to be involved in the maintenance of acidity within secretory vesicles (62). Previously, it was demonstrated that whole body knock-out of ATP6ap2 was lethal in mice (63); whereas, tissue specific knock-out studies of ATP6ap2 in cardiomyocytes or in podocytes resulted in detrimental defects after birth including heart failure or renal failure, respectively (64,65).…”

Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation

“…24 (Pro)renin receptor-bound renin and prorenin display increased enzymatic activity, and binding activates intracellular signaling, upregulating the expression of profibrotic proteins. 25,26 However, new data now suggest that (pro)renin receptor is functionally linked to the vacuolar proton-ATPase [27][28][29] ; therefore, the role of (pro) renin receptor as a part of the RAS remains controversial. The independent identification of possible intracellular isoforms of renin in rodents and humans provides further support for alternative mechanisms that act to locally generate A-II and to partition the local and systemic effects of the hormone.…”

ATP6AP2/(Pro)renin Receptor Contributes to Glucose Metabolism via Stabilizing the Pyruvate Dehydrogenase E1 β Subunit

“…On the other hand, v-ATPase is a multisubunit proton pump involved in diverse and fundamental cellular physiology, and v-ATPasemediated acidification, requiring its accessory unit Atp6ap2, was shown to play a pivotal role in canonical and noncanonical Wnt signaling pathways (14 -16). Furthermore, several studies on conditional knock-out mice specific for the heart and kidney cells revealed that Atp6ap2 is essential for v-ATPase-associated autophagy, leading to the maintenance of cell structure and survival (17)(18)(19). More recently, we have shown that Atp6ap2 interacts with partitioning defective 3 homolog, one of the major cell polarity determinants, and contributes to laminar formation during retinal development in mice (20).…”