Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor ((P)RR) blockade with HRP has been reported to exerts beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefit on top of RAS blockade is still unknown. Here we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels (allowing continuous (P)RR stimulation in vivo), with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels, and diminished renal (P)RR and AT1 receptor expression. It also suppressed plasma and tissue RAS activity, and suppressed cardiac ANP and BNP expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity or aldosterone. Yet, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia and increased plasma plasminogen activator-inhibitor 1, renal cyclo-oxygenase-2 and the cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might in fact act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable.