Cardiovascular and non-cardiovascular functions of the (pro)renin receptor (PRR)
Our understanding of the role of the prorenin receptor (PRR) in physiology and pathology has changed dramatically. Initially it was believed that the PRR is a cardiovascular receptor, involved in regulating the renin-angiotensin system. However, recent data (by others and us) demonstrates a fundamental non-cardiovascular role of the PRR. In collaboration with Michael Bader (MDC), we have determined that complete knockout of PRR in mouse embryonic stem cells, fails to generate chimeras when injected into blastocysts, indicating an important role for this protein in cellular development. We have subsequently initiated several PRR tissue-specific conditional knockout models. Generation of podocyte-specific PRR knockout mice (cKO) resulted in the death of the animals ~2-3 weeks after birth. Within 14 days, these cKO animals developed nephrotic syndrome andalbuminuria, due to podocyte foot process fusion and cytoskeletal changes. Our in vivo and in vitro findings indicated a functional block in autophagosome-lysosome fusion and overload of the proteasome protein degradation machinery. These results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein turnover machinery. We are now investigating the effect of PRR deletion in other cell types, namely T cells, pancreatic b-cells and renin-producing cells. Interestingly, the PRR also exists as a soluble receptor (sPRR), and it has been hypothesized that this sPRR may have an important biological role. We have developed a sensitive ELISA to quantitate sPRR in biological fluids, and we are currently investigating if sPRR levels may be an important biomarker for cardiovascular disease and cancer.