Molecular mechanisms of relaxin in renal fibrosis

Abstract

Renal fibrosis (scarring) is a hallmark of chronic kidney disease and is characterized by an excessive accumulation of extracellular matrix (ECM) proteins, primarily collagen. Driven by the continuous exposure to pathological stimuli and/or pro-fibrotic cytokines, fibrosis is a consequence of an imbalance between myofibroblast-induced ECM synthesis (fibrogenesis) and matrix metalloproteinase (MMP)-induced degradation (fibrolysis). Failure to resolve the progression of fibrosis causes significant organ dysfunction and the onset of failure. Angiotensin (Ang) II and transforming growth factor (TGF)-β1 are amongst the most potent cytokines that drive this pathological condition. To date, there are no effective treatments to prevent the ensuing structural and functional changes caused by fibrosis, with dialysis or transplantation as the only option for patients with end-stage kidney disease.

The pregnancy-related hormone, relaxin, is now increasingly recognized as a rapid-occurring but safe anti-fibrotic agent. Relaxin has been consistently shown to inhibit Ang II- or TGF-β1-stimulated renal collagen deposition from numerous human and rodent fibroblast culture models in vitro, and in several experimental models of renal fibrosis in vivo, regardless of etiology. The anti-fibrotic properties of relaxin were found to be primarily mediated through its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1) and via inhibition of TGF-β1-stimulated myofibroblast differentiation and myofibroblast-induced aberrant matrix/collagen synthesis, while promoting the expression/activity of several MMPs that can mediate collagen degradation.