Evaluation of a Combination Therapy of Bone Marrow-Derived Stem Cells and Serelaxin Against Established Renal Fibrosis in Normotensive and Hypertensive Models of Disease

Fibrosis significantly impairs the viability and therapeutic efficacy of stem cell-based therapies. To overcome this, we demonstrated that the anti-fibrotic drug, serelaxin (recombinant human relaxin; RLX), could prevent renal fibrosis progression in a unilateral ureteric obstruction (UUO)-induced murine model of interstitial renal disease and improve the ability of injected human bone marrow-derived mesenchymal stem cells (BM-MSCs) to attenuate renal injury. To advance the therapeutic potential of this combination therapy, we have now investigated its effects as an intervention therapy in the UUO model, and in a uninephrectomised/deoxycorticosterone acetate/drinking saline water (1K/DOCA/salt) model of hypertension. 7-8 week old male C57B6J mice were subjected to UUO or 1K/DOCA/salt (2.4mg/day, s.c; 21 days). Sub-groups of injured mice (n=6/group) were administered RLX (0.5mg/kg/day; s.c) alone, BM-MSCs (1x10 6 /mouse; i.v) alone or both combined 3-days post-UUO or 14 days post-1K/DOCA/salt-treatment. Untreated injured mice and sham-operated or 1K-mice were included as respective controls. Mice were killed 10 days post-UUO or 21 days post-1K/DOCA/salt treatment (7 days post-intervention) for tissue collection and analysis. UUO- and 1K/DOCA/salt-injured mice underwent significant renal damage, inflammation and (interstitial and total collagen-induced) fibrosis at the time-points studied, as determined by histological and biochemical analyses (all p<0.01 vs respective uninjured controls). All 1K/DOCA/salt-treated mice had systolic blood pressure levels of 140-150mmHg over the experimental period, compared to 1K-mice having 115-120mmHg (as measured by tail cuff plethysmography; p<0.01). Unlike BM-MSCs alone, the combined effects of BM-MSCs and RLX significantly reduced established UUO-induced renal damage and fibrosis, primarily by reducing myofibroblast-induced collagen deposition (all p<0.05 vs BM-MSCs alone). Treatment-induced effects of the hypertensive model are currently being evaluated and will be presented. These findings confirm that agents that can effectively reduce established fibrosis can enhance the therapeutic potential of BM-MSCs in treating kidney diseases, when added in combination.