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 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.

Adapting the Scar-in-a-Jar to Skin Fibrosis and Screening Traditional and Contemporary Anti-Fibrotic Therapies

“…This has been shown to suppress not only Smad 2/3 and consequently, TGF β 1 signalling pathways in cardiac fibroblasts, but also angiotensin II type 2 receptors and interleukin-1 β and the potential interaction of these signalling pathways with the TGF β axis ( Yuan et al, 2017 ; Wu et al, 2018 ), as well as with the inflammasome ( Pinar et al, 2020 ). In addition to those, RLX-2 can increase the expression and activity of matrix metalloproteinases that facilitate ECM degradation ( Li et al, 2021 ). Its application in other diseases, mainly fibrotic, has been postulated, although the clinical trials have been inconclusive on its therapeutic efficacy ( Samuel et al, 2017 ; Yuan et al, 2017 ; Blessing et al, 2019 ; Hinz and Lagares, 2020 ).…”

Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

“…Activation of immune cells and NLRP3 inflammasomes have both been implicated in many chronic inflammatory conditions, including hypertension and the associated kidney injury [ 77 ]. BM-MSCs were found to suppress the high-salt-induced assembly and activation of NLRP3 inflammasomes (including NLRP3 and caspase 1) and the downstream production of IL-1β in Dahl salt-sensitive rats and 1K/DOCA/salt-injured mice and inhibit innate (macrophages) and adaptive immune (T cells) components in a murine model of fibrotic nephropathy induced by unilateral ureteral obstruction (UUO) [ 71 ] and 1K/DOCA/salt-induced hypertensive mice [ 72 , 78 ]. Therefore, the ability of BM-MSCs to inhibit inflammasome activity and immune cell infiltration may also explain the anti-hypertensive and anti-inflammatory effects of these stem-cell-based therapies.…”

“…More recently, evidence has emerged of a novel approach to improve the fibrotic microenvironment of chronically injured kidneys into which BM-MSCs can be administered to improve their survival, migration to site(s) of damage, and reparative efficacy. Recent studies have demonstrated that combining BM-MSCs with the anti-fibrotic and renoprotective agent serelaxin [ 20 , 71 , 72 , 78 ] might provide a more promising alternative (to the strategies described above) to enhance the therapeutic efficacy of BM-MSCs as a treatment for CKD, which is discussed further in the next section.…”

“…Based on these findings, which identified endogenous relaxin as a naturally-occurring regulator of collagen turnover, a recombinant form of human relaxin-2 (also known as serelaxin; which is also referred to as RLX) was developed to evaluate the anti-fibrotic potential of RLX, which was found to be bioactive in several other species including rodents [ 119 ]. RLX has consistently demonstrated promising and rapidly acting anti-fibrotic efficacy in various experimental CKD models regardless of etiology, by either preventing fibrogenesis or effectively attenuating established tubulointerstitial fibrosis and glomerulosclerosis [ 71 , 72 , 78 , 120 , 121 , 122 , 123 , 124 , 125 ], leading to improved kidney function.…”

“…The combined effects of RLX (0.5 mg/kg/day; a dose frequently used to induce its anti-fibrotic and other organ-protective effects [ 71 , 72 , 78 , 126 , 128 ]; subcutaneously (sc) administered via slow-release osmotic minipumps) and BM-MSCs (1 × 10 6 /mouse, delivered via the intrarenal vein 15–30 min after RLX administration) completely attenuated fibrosis progression in normotensive mice subjected to one week of unilateral ureteric obstruction (UUO)-induced tubulointerstitial fibrotic disease in vivo [ 71 ] ( Table 4 ). This was to a greater extent than the effects of BM-MSCs (which did not induce any anti-fibrotic effects alone) or RLX (which only partially attenuated kidney fibrosis) alone over the 7-day treatment period.…”