Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats

Abstract

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 handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, 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 as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and 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.

Combined Renin Inhibition/(Pro)Renin Receptor Blockade in Diabetic Retinopathy- A Study in Transgenic (mREN2)27 Rats

“…The putative (P)RR blocker HRP did not provide add-on beneficial effects when combined with aliskiren, nor counteracted the effects of aliskiren in the retina of diabetic mRen2 rats. The latter contrasts with earlier observations in the kidney of diabetic mRen2 rats, where HRP counteracted the beneficial effects of aliskiren [47]. The former agrees with our in-vitro studies in Müller cells, showing prorenin-induced effects that are entirely Ang II-dependent.…”

“…STZ-induced diabetes mellitus increased blood glucose levels ∼5-fold, and treatment with aliskiren or aliskiren+HRP did not alter this. Aliskiren lowered MAP in Ren2 rats from 123±4 mmHg to 104±5 mm Hg, and this effect was unaltered by simultaneous administration of HRP [47].…”

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

“…Similarly, HRP does not show a protective effect in the clipped kidney, Goldblatt hypertensive rat model (Krebs, et al, 2008). Moreover, in diabetic TGR(mREN2)27 rats, a well-established nephropathy model characterized by high prorenin levels, HRP was shown to counteract the beneficial effects of aliskiren in the kidney, induce hyperkalemia, and increase plasma plasminogen activator-inhibitor 1, renal COX-2, and cardiac collagen content (te Riet, et al, 2014). A recent study showed that HRP may actually have an agonistic effect upon binding to the PRR, increasing phosphorylation of ERK1/2 in the retina (Wilkinson-Berka, Heine, et al, 2010).…”

The Effect of Combined Treatment with the (Pro)Renin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats

“…In contrast, only ACE inhibition could ameliorate ERK1/2 phosphorylation. It has been reported that HRP might also exert partial agonist effect on (P) RR, apart from the receptor blockade [34]. This could explain why HRP did not influence the diabetes-induced ERK phosphorylation in our study.…”