Timothy L Reudelhuber1. 1. Laboratory of Molecular Biochemistry of Hypertension, Institut de Recherches Cliniques de Montreal and Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. reudelt@ircm.qc.ca
Abstract
PURPOSE OF REVIEW: Elevated prorenin levels are seen in diabetics with microvascular disease. The discovery of a receptor capable of binding renin and prorenin [(P)RR] and triggering an intracellular signal in the laboratory setting raised the expectation that prorenin might be directly responsible for these vascular disorders. However, there has been substantial disagreement concerning the signaling properties of renin and prorenin and it has been impossible to inactivate the (P)RR gene in mouse to define its function. RECENT FINDINGS: Mouse and rat models in which prorenin is highly overexpressed do not demonstrate the glomerulosclerosis typically seen in severe diabetic nephropathy, but do exhibit an increase in blood pressure that is angiotensin II-dependent. (P)RR has been shown to colocalize with other subunits of the vacuolar ATPase in the kidney and heart and to be necessary for Wnt signaling in a renin-independent manner. Although whole-body inactivation of the (P)RR gene is lethal, tissue-specific inactivation results in severe disorders associated with massive cell death. SUMMARY: These results do not support a role of direct prorenin or renin signaling through (P)RR in vascular disorders. Rather, they suggest that the main role of (P)RR is as a subunit of the vacuolarATPase complex. Whether or not (P)RR is responsible for the ability of prorenin to generate angiotensin II in tissues has not been resolved.
PURPOSE OF REVIEW: Elevated prorenin levels are seen in diabetics with microvascular disease. The discovery of a receptor capable of binding renin and prorenin [(P)RR] and triggering an intracellular signal in the laboratory setting raised the expectation that prorenin might be directly responsible for these vascular disorders. However, there has been substantial disagreement concerning the signaling properties of renin and prorenin and it has been impossible to inactivate the (P)RR gene in mouse to define its function. RECENT FINDINGS:Mouse and rat models in which prorenin is highly overexpressed do not demonstrate the glomerulosclerosis typically seen in severe diabetic nephropathy, but do exhibit an increase in blood pressure that is angiotensin II-dependent. (P)RR has been shown to colocalize with other subunits of the vacuolar ATPase in the kidney and heart and to be necessary for Wnt signaling in a renin-independent manner. Although whole-body inactivation of the (P)RR gene is lethal, tissue-specific inactivation results in severe disorders associated with massive cell death. SUMMARY: These results do not support a role of direct prorenin or renin signaling through (P)RR in vascular disorders. Rather, they suggest that the main role of (P)RR is as a subunit of the vacuolarATPase complex. Whether or not (P)RR is responsible for the ability of prorenin to generate angiotensin II in tissues has not been resolved.
Authors: Nilima Biswas; Adam X Maihofer; Saiful Anam Mir; Fangwen Rao; Kuixing Zhang; Srikrishna Khandrika; Manjula Mahata; Ryan S Friese; C Makena Hightower; Sushil K Mahata; Dewleen G Baker; Caroline M Nievergelt; Sucheta M Vaingankar; Daniel T O'Connor Journal: BMC Med Genet Date: 2016-03-11 Impact factor: 2.103
Authors: Sebastian Kirsch; Eva Schrezenmeier; Sabrina Klare; Daniela Zaade; Kerstin Seidel; Jennifer Schmitz; Sarah Bernhard; Dilyara Lauer; Mark Slack; Petra Goldin-Lang; Thomas Unger; Frank S Zollmann; Heiko Funke-Kaiser Journal: Int J Mol Med Date: 2014-01-14 Impact factor: 4.101