New targets for renal interstitial fibrosis: relaxin family peptide receptor 1-angiotensin type 2 receptor heterodimers.

The signal transduction mechanisms involved in the renoprotective effects of relaxin are not well understood. Chow et al. demonstrate that relaxin family peptide receptor 1 (RXFP1) forms heterodimer complexes with the angiotensin type 2 receptor (AT2), even in the absence of ligand, and that these heterodimers are required for relaxin's antifibrotic effects. These findings identify a previously unknown link between relaxin and angiotensin II signaling that could be a potential new target for slowing the progression of fibrotic renal diseases.

Relaxin is a small peptide in the insulin family that has been well characterized for its role in pregnancy, and recent studies have examined the beneficial effects of this hormone in cardiovascular and fibrotic diseases (1). Indeed, results of a phase III clinical trial demonstrated that Serelaxin (recombinant human relaxin -2) treatment improves symptoms and 180-day survival in patients treated for acute heart failure (2). In addition to the vasodilatory effects of relaxin, the hormone also has potent anti-fibrotic effects in experimental models of renal disease (3); however, the signaling mechanisms involved in the protective effects of relaxin have not yet been completely identified.

The renoprotective effects of relaxin have been demonstrated in various experimental models. Deletion of the relaxin gene in male mice results in renal hypertrophy dysfunction and fibrosis, and administration of exogenous relaxin to these mice reversed the glomerular sclerosis and tubulointerstitial fibrosis in these animals (4). In addition, relaxin treatment of aged Munich Wistar rats with established structural injury and decreased renal function reversed the functional decline and structural damage seen in the aging rat (5). Renal anti-fibrotic effects of relaxin have also been observed in models of renal mass reduction, angiotensin II induced hypertension, papillary necrosis, and antiglomerular basement membrane disease as recently reviewed (3). Thus, targeting the relaxin pathway may have great therapeutic potential in the treatment of fibrotic kidney diseases.

In this issue of Kidney International, Chow and colleagues (6) identify the AT2 receptor as a critical player for the protective effects of relaxin. Although relaxin was not shown to directly interact with the AT2 receptor itself, these investigators found that the antifibrotic effects of relaxin in both in vivo and in vitro models rely on heterodimerization of the RXFP-1 and AT2 receptors. Previous studies by this group have provided insights into the signaling pathways through which relaxin exerts its anti-fibrotic effects within the kidney, and these findings have linked relaxin with two well known factors in the regulation of renal fibrosis: nitric oxide and transforming growth factor β (TGF-β). Nitric oxide is an essential factor in maintaining renal health (7), and in renal myofibroblasts, relaxin binds to the RXFP-1 receptor, activates G proteins and phosphorylates ERK1/2 to stimulate increased expression of nitric oxide synthase 1 (NOS1, neuronal NOS) (8). On the other hand, TGF-β contributes to progressive renal fibrosis and structural damage in the glomeruli, tubulointerstitium and tubules of the kidney (9), and studies have shown that relaxin, likely via a NOS 1 dependent pathway, can inhibit pro-fibrotic TGF-β signaling via reductions in Smad2 signaling (10,11).

The current study by Chow et al identifies a previously unknown role for the AT2 receptor in relaxin signaling (6). By using either an AT2 antagonist or AT2 deficient mice, these authors demonstrated that the actions of relaxin on NO and TGFβ signaling as well as the anti-fibrotic effects of relaxin were completely lost both in vivo and in vitro when the AT2 receptor was inhibited or absent. This finding has several implications for the understanding the actions of relaxin in disease states where the AT2 receptor is upregulated and suggests that the abundance of AT2 receptors can determine the efficacy of relaxin treatment. The authors also speculate that the RXFP1 – AT2 heterodimers may also act to antagonize AT1 receptor activation, thereby providing an additional mechanism by which activation of the relaxin pathway may be beneficial in renal disease (See Figure 5, of the subject paper of this commentary [reference 6] Page XX this issue.). Improved understanding of the interactions between relaxin, the AT2 receptors and the classical renin angiotensin system in the setting of renal fibrosis will help to define the therapeutic potential of the relaxin pathway in chronic kidney disease.