Therapeutic Renin Inhibition in Diabetic Nephropathy—A Review of the Physiological Evidence

Frontiers in Physiology ◽

10.3389/fphys.2020.00190 ◽

2020 ◽

Vol 11 ◽

Author(s):

Bianca Domingues Massolini ◽

Stephanie San Gregorio Contieri ◽

Giulia Severini Lazarini ◽

Paula Antoun Bellacosa ◽

Mirela Dobre ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Physiological Evidence ◽

Renin Inhibition

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

AJP Renal Physiology ◽

10.1152/ajprenal.00010.2014 ◽

2014 ◽

Vol 306 (10) ◽

pp. F1179-F1189 ◽

Cited By ~ 11

Author(s):

Luuk te Riet ◽

Mieke van den Heuvel ◽

Carine J. Peutz-Kootstra ◽

Joep H. M. van Esch ◽

Richard van Veghel ◽

...

Keyword(s):

Blood Pressure ◽

Diabetic Nephropathy ◽

Natriuretic Peptide ◽

Partial Agonist ◽

Receptor Expression ◽

Plasminogen Activator Inhibitor 1 ◽

Independent Manner ◽

Beneficial Effects ◽

Renin Inhibition

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.

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