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

Background and Purpose Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to 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) could therapeutically reduce renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)‐induced hypertension, compared with the effects of the ACE inhibitor, perindopril. Experimental Approach Adult male C57BL/6 mice were uni‐nephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt) for 21 days. Control mice were uni‐nephrectomised but received water over the same time period. Sub‐groups of 1K/DOCA/salt‐injured mice (n = 5–8 per group) were treated with either serelaxin (0.5 mg·kg−1·day−1) or BM‐MSCs (1 × 106 per mouse) alone; both treatments combined (with 0.5 × 106 or 1 × 106 BM‐MSCs per mouse); or perindopril (2 mg·kg−1·day−1) from days 14–21. Key Results 1K/DOCA/salt‐injured mice developed elevated BP and hypertension‐induced renal damage, inflammation and fibrosis. BM‐MSCs alone reduced the injury‐induced fibrosis and attenuated BP to a similar extent as perindopril. Serelaxin alone modestly reduced renal fibrosis and effectively reduced tubular injury. Strikingly, the combined effects of BM‐MSCs (at both doses) with serelaxin significantly inhibited renal fibrosis and proximal tubular epithelial injury while restoring renal architecture, to a greater extent than either therapy alone, and over the effects of perindopril. Conclusion and Implications Combining BM‐MSCs and serelaxin provided broader renoprotection over either therapy alone or perindopril and might represent a novel treatment for hypertensive CKD.