Objective Renal function in patients with diabetes mellitus (DM) might be influenced by the level of prorenin due to its binding to the (pro)renin receptor ((P)RR) and the subsequently occurring angiotensin production and/or the direct agonistic effects of prorenin mediated via this receptor. Indeed, in DM elevated prorenin levels are correlated with the development of microvascular complications such as nephropathy.
Design and Methods In this study we evaluated renal function in diabetic TGR(mREN2)27 rats (a high prorenin hypertensive model), treated with vehicle, the renin inhibitor aliskiren, or aliskiren plus the putative (P)RR antagonist HRP for 3 weeks. 24-hour urine was collected, and blood and kidney were evaluated for renin-angiotensin system components and pathology.
Results Increased diuresis and proteinuria due to DM were prevented by aliskiren, but not aliskiren+HRP. Aliskiren+HRP additionally decreased creatinine clearance, and increased the plasma levels of the profibrotic marker plasminogen-activator inhibitor-1. The increased natriuresis and renal collagen-1 expression in this model were unaffected by aliskiren±HRP. Aliskiren increased rat renin expression in the renal cortex. This was associated with a decline in (P)RR and AT1 receptor mRNA expression, and these changes were unaffected by HRP. Glomerular volume and interlobar arterial lumen diameter modestly increased in the aliskiren+HRP group, and were unaffected by aliskiren alone.
Conclusions HRP, when given on top of aliskiren in DM TGR(mREN2)27 rats worsens kidney damage and counteracts the beneficial effects of aliskiren. (P)RR blockade is therefore contraindicated in DM.