Differences in the renal antifibrotic cGMP/cGKI-dependent signaling of serelaxin, zaprinast, and their combination

Abstract

Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive antifibrotic effects compared to the monotherapy. Due to antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for antifibrotic signaling of zaprinast.

Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways

“…However, clinical trials using (se)relaxin or mimetics are needed to determine if this pathway can be exploited to treat human fibrotic disease. (Chow et al, 2012;Chow et al, 2014;Mookerjee et al, 2009;Sarwar et al, 2015;Wang et al, 2016;Wetzl et al, 2017;Wetzl et al, 2016 (Hossain et al, 2016;Praveen et al, 2017) Relaxin-3 RXFP1, RXFP3? Cardiac fibrosis unknown NLRP3-inflammasome Collagen MMPs (Hossain et al, 2011;Zhang et al, 2018;Zhang et al, 2017) InsL6 unknown Cardiac fibrosis unknown TGFβ collagen (Maruyama et al, 2018)…”

“…In comparison, the phosphodiesterase-5 (PDE5) inhibitor, zaprinast, acts as an antifibrotic agent via suppression of ERK1/2 signaling, but this effect was independent from PKG1. The combination of serelaxin with this PDE5 inhibitor does not reveal additional benefits against kidney fibrosis (Wetzl et al, 2017).…”

Current Concepts on the Reno-Protective Effects of Phosphodiesterase 5 Inhibitors in Acute Kidney Injury: Systematic Search and Review

“…The main characteristics and results of the human studies evaluating the potential reno-protective effects of PDE5Is are summarized in Table 1 [17,24,38,39]. The main characteristics and results of the animal studies on currently proposed AKI models evaluating the potential reno-protective effects of sildenafil, tadalafil, icariin, vardenafil, zaprinast-udenafil are summarized in Table 2 [23,30,, Table 3 [29,35,45,49,[62][63][64][65][66][67][68][69][70][71][72][73][74], Table 4 [18,75,76], Table 5 [45,77,78], and Table 6 [21,40,79,80], respectively. The main characteristics and results of the animal studies in the AKI-CKD transition spectrum (focusing on renal function and/or structure alterations for up to three months, not fulfilling the KDIGO definition for CKD [6]) evaluating the potential reno-protective effects of sildenafil, tadalafil, icariin, vardenafil, zaprinast-udenafil are summarized in Table A1 [109,110], respectively (Appendix B).…”

Impact of the NO-Sensitive Guanylyl Cyclase 1 and 2 on Renal Blood Flow and Systemic Blood Pressure in Mice

“…NO-GC is the main target mediating the modulatory effects of nitric oxide in the kidney. Recent studies demonstrated that the NO-GC plays an important role in the pathogenesis of chronic kidney disease through both hemodynamic and direct pro-fibrotic effects [ 15 , 17 , 19 , 20 , 21 ]. However, the two distinct NO-GC isoforms have indistinguishable enzymatic properties and isoform-specific inhibitors are lacking.…”