Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension

Jennifer M. Sasser, Mark W. Cunningham, Chris Baylis

Research output: Contribution to journalArticlepeer-review

Abstract

Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose an-giotensin (ANG) II (400 ng-kg-1-min-1 sc) for 6 wk or shams. RLX was administered (4 (ug/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg-day-1.100 g-1, P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohy-drolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects.

Original languageEnglish
Pages (from-to)F1355-F1362
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number12
DOIs
StatePublished - 15 Dec 2014

Keywords

  • Dimethylarginine dimethylaminohydrolase
  • NADPH oxidase
  • Nitric oxide
  • Protein arginine methyltransferase-1

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