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

Yifang Li, Matthew Shen, Dorota Ferens, Brad R.S. Broughton, Padma Murthi, Sheetal Saini, Robert E. Widdop, Sharon D. Ricardo, Anita A. Pinar, Chrishan S. Samuel

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12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1164-1181
Number of pages18
JournalBritish Journal of Pharmacology
Volume178
Issue number5
DOIs
Publication statusPublished - Mar 2021

Keywords

  • chronic kidney disease
  • combination therapy
  • fibrosis
  • hypertension
  • mesenchymal stem cells
  • relaxin

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