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

Luuk te Riet, Mieke van den Heuvel, Carine J. Peutz-Kootstra, Joep H. M. van Esch, Richard van Veghel, Ingrid M. Garrelds, Usha Musterd-Bhaggoe, Angelique M. Bouhuizen, Frank P. J. Leijten, A. H. Jan Danser, Wendy W. Batenburg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 reno-protective 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.
Original languageEnglish
Pages (from-to)F1179-F1189
JournalAmerican Journal of Physiology-Renal Physiology
Issue number10
Publication statusPublished - May 2014


  • prorenin
  • diabetes
  • renin inhibition
  • (pro)renin receptor blockade
  • kidney


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