Combining mesenchymal stem cells with serelaxin provides enhanced renoprotection against 1K/DOCA/salt‐induced hypertension

Abstract

Background and Purpose Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to nephron loss and renal dysfunction, and impairs the efficacy of stem cell‐based therapies. This study determined whether combining bone marrow‐derived mesenchymal stem cells (BM‐MSCs) with the renoprotective effects of recombinant human relaxin (serelaxin, RLX) could therapeutically reduce established renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)‐induced hypertension; in comparison to an angiotensin converting enzyme inhibitor (ACEi). Experimental Approach Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate (2.4mg/kg/day), and saline to drink (1K/DOCA/salt), for 21 days. Control mice were uninephrectomised but received water over the same time‐period. Sub‐groups of 1K/DOCA/salt‐injured mice (n=5‐8/group) were treated with either RLX (0.5mg/kg/day) or BM‐MSCs (1x10⁶/mouse) alone; both treatments combined (with 0.5x10⁶ or 1x10⁶ BM‐MSCs/mouse); or the ACEi, perindopril (2mg/kg/day), from days 14‐21. Key Results 1K/DOCA/salt‐injured mice developed elevated blood pressure and hypertension‐induced renal damage, inflammation and fibrosis. BM‐MSCs alone reduced the injury‐induced interstitial fibrosis and total collagen deposition, and attenuated blood pressure to a similar extent as perindopril. RLX alone modestly reduced renal fibrosis and effectively reduced tubular injury. Strikingly, the combined effects of BM‐MSCs (at both doses) with RLX significantly abrogated renal fibrosis and proximal tubular epithelial injury whilst restoring renal architecture, to a greater extent than either therapy alone, and over the effects of the clinically‐used ACEi. Conclusions & Implications The combined effects of BM‐MSCs and RLX provided broader renoprotection over either therapy alone or perindopril, and might represent a novel treatment for hypertensive CKD.