Relaxin: exploring the antifibrotic potential of a pregnancy hormone.

Excess accumulation of extracellular matrix proteins has been well recognized as a key feature of chronic kidney diseases. Renal fibrosis, particularly tubulointerstitial fibrosis, parallels the progressive loss of organ function, which ultimately leads to overt renal failure and the need for dialysis. Driven by distinct causes like hypertension, chronic inflammation, elevated blood glucose, or postrenal obstruction, development of kidney fibrosis is mediated and fine-tuned by a variety of cytokines, growth factors, and soluble factors. Among others, transforming growth factor-beta (TGF-b) is of pivotal importance because of its ability to regulate both matrix protein synthesis and degradation in a distinctive profibrotic manner. As the knowledge about TGF-b and matrix protein biology and pathophysiology has substantially increased over the recent years, new strategies to tackle renal fibrosis have been developed that are centered around the cascade of TGF-b generation, TGF-b signaling, and matrix protein deposition and degradation. An emerging novel therapeutic approach to target fibrosis is relaxin, a small peptide hormone that is endogenously produced by corpus luteum of the ovary. The name relaxin is derived from its unique ability to soften connective tissue of the reproductive tract in pregnancy (i.e., to relax the cervix and the pubic ligament to facilitate delivery) [1]. Relaxin has received additional interest because it mediates the profound vascular effects seen in pregnancy, too. The general hemodynamic changes and, especially, the changes in renal hemodynamics in pregnancy (decline in renal vascular resistance, increase in renal plasma flow and GFR) are mediated in large parts by relaxin through actions on nitric oxide and endothelin receptor B activation [1, 2]. Of particular interest to nephrologists, relaxin blocks the renal hemodynamic effects of angiotensin II independently of pregnancy [3]. These vascular effects appear largely dependent on the activation of matrix-metalloproteases (MMP), enzymes that digest and remove collagens and other matrix proteins [1, 2, 4]. Activation of MMPs by relaxin has been