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

• Published in: American journal of physiology. Renal physiology Vol. 307; no. 12; pp. F1355 - F1362
• Main Authors: Sasser, Jennifer M, Cunningham, Jr, Mark W, Baylis, Chris
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.12.2014
• Subjects: Angiotensin II; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - pharmacology; Antioxidants - administration & dosage; Antioxidants - pharmacology; Arginine - analogs & derivatives; Arginine - blood; Arterial Pressure - drug effects; Chemicals; Dinoprost - analogs & derivatives; Dinoprost - metabolism; Disease Models, Animal; Down-Regulation; Humans; Hypertension; Hypertension - blood; Hypertension - chemically induced; Hypertension - physiopathology; Hypertension - prevention & control; Injections, Subcutaneous; Kidney - drug effects; Kidney - metabolism; Liver - drug effects; Liver - metabolism; Male; NADPH Oxidases - metabolism; Nitric oxide; Nitric Oxide - metabolism; Oxidative stress; Oxidative Stress - drug effects; Plasma; Prescription drugs; Proteinuria - chemically induced; Proteinuria - metabolism; Proteinuria - prevention & control; Rats, Sprague-Dawley; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Relaxin - administration & dosage; Relaxin - pharmacology; Thiobarbituric Acid Reactive Substances - metabolism; dimethylarginine dimethylaminohydrolase; nitric oxide; protein arginine methyltransferase-1; NADPH oxidase
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00407.2014

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 angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/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-dimethylaminohydrolase (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.