Abstract

Serelaxin, a recombinant form of the naturally occurring peptide hormone relaxin-2, is a pleiotropic vasodilating hormone that has been studied in patients with acute heart failure. In this study, the effects of serelaxin on cardiac and renal function, fibrosis, inflammation and lipid accumulation were studied in DOCA-salt treated rats. Uninephrectomized rats were assigned to two groups: controls provided with normal drinking water and DOCA provided with DOCA pellets and sodium chloride drinking water. After 4 weeks, the DOCA-salt rats were randomly selected and implanted with osmotic minipumps delivering vehicle or serelaxin for another 4 weeks. Treatment with serelaxin prevented cardiac and renal dysfunction in DOCA-salt rats. Serelaxin prevented cardiac and renal fibrosis, as determined by Picrosirius Red staining and Second Harmonic Generation (SHG) Microscopy. Treatment of DOCA-salt rats with serelaxin decreased renal inflammation, including the expression of TGF-β, NFκB, MCP-1, IL-1, IL-6, ICAM-1, VCAM-1 and CD68 macrophages. Serelaxin also decreased lipid accumulation in kidney in part by decreasing SREBP-1c, SREBP-2, ChREBP, FATP1, HMGCoAR, and LDL receptor, and increasing Acox1 and ABCA1. In summary, serelaxin reversed DOCA-salt induced cardiac and renal dysfunction.

Highlights

  • Chronic kidney disease (CKD) affects more than 10% of the population worldwide and its prevalence is increasing[1]

  • The systolic blood pressure was increased in deoxycorticosterone acetate (DOCA)-salt rats compared with control rats, whereas serelaxin normalized the increased systolic blood pressure in DOCA-salt rats at 4 weeks after DOCA implantation[19, 20] (Table 1)

  • In non-hypertension model, there are preclinical and clinical data demonstrated the impact of serelaxin treatment on heart and kidney function and protection

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Summary

Introduction

Chronic kidney disease (CKD) affects more than 10% of the population worldwide and its prevalence is increasing[1] It consists of a diverse range of etiologies, including immunological, mechanical, metabolic and toxic insults, among others. Relaxin is a 6 kDa peptide hormone which mediates many adaptive hemodynamic changes that occur during pregnancy, such as increased cardiac output, increased renal blood flow, and increased arterial compliance[3] In the female, it is produced by the corpus luteum of the ovary and breast during pregnancy, by the placenta, chorion, and decidua[4]. A recombinant form of the human peptide relaxin-2, is a pleiotropic vasodilating hormone that has been studied in patients with acute heart failure[7] It mediates vasodilation by increasing the production of nitric oxide (NO), a potent vasodilator. Serelaxin is a potential treatment for renal dysfunction in cirrhosis[18]

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