Serelaxin attenuates renal inflammation and fibrosis in a mouse model of dilated cardiomyopathy

Abstract

New Findings What is the central question of this study?The aim was to determine the renoprotective effects of serelaxin in the setting of chronic heart failure. What are the main findings and its importance?Our data indicate that serelaxin can reduce renal fibrosis and inflammation in experimental heart failure. Currently, there are no effective treatments to rescue renal function in heart failure patients, and our data suggest that serelaxin might have the potential to reduce renal fibrosis and inflammation in heart failure. Abstract Serelaxin has been demonstrated to attenuate renal fibrosis and inflammation in cardiorenal disease. In the present study, we tested the hypothesis that serelaxin can prevent the decline in renal function in dilated cardiomyopathy (DCM) by targeting renal fibrosis and inflammation. Male transgenic mice with DCM (n = 16) and their wild‐type littermates (WT; n = 20) were administered either vehicle or serelaxin (500 μg kg−1 day−1; subcutaneous minipumps; 8 weeks). Cardiac function was assessed via echocardiography before and during the eighth week of serelaxin treatment. Renal function and inflammation as well as cardiac and renal fibrosis were assessed at the end of the study. Serelaxin had minimal effect on cardiac function (P ≥ 0.99). Tubulointerstitial and glomerular fibrosis were ∼3‐fold greater in vehicle‐treated DCM mice compared with vehicle‐treated WT mice (P ≤ 0.001). Renal mRNA expression of Tnfα and Il1α were ∼4‐ and ∼3‐fold greater, respectively, in vehicle‐treated DCM mice compared with vehicle‐treated WT mice (P ≤ 0.05). Tubulointerstitial and glomerular fibrosis were 46 and 45% less, respectively, in serelaxin‐treated DCM mice than in vehicle‐treated DCM mice (P ≤ 0.01). Renal cortical mRNA expression of Tnfα and Il1α were 56 and 58% less, respectively, in the former group compared with the latter (P ≤ 0.05). The urinary albumin:creatinine ratio was ∼3‐fold greater in vehicle‐treated DCM mice compared with vehicle‐treated WT mice (P = 0.02). The urinary albumin:creatinine ratio was not significantly different between vehicle‐treated DCM mice and serelaxin‐treated DCM mice (P = 0.38). These data suggest that serelaxin can attenuate renal fibrosis and inflammation and has the potential to exert renoprotective effects in DCM.

Distinct Phenotypes Induced by Three Degrees of Transverse Aortic Constriction in Mice

“…In addition to cardiac phenotypes, we observed renal atrophy in mice subjected to 27G TAC. Renal atrophy was reported in a mouse model of dilated cardiomyopathy, with increased tubulointerstitial and glomerular fibrosis, alongside reduced renal function 34 . Since chronic heart failure can promote chronic kidney failure in both humans and in mouse studies 35 , we decided to investigate this phenotype further and found renal atrophy secondary to 27G TAC, in the absence of renal dysfunction.…”

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage

“…The half life time of Serelaxin in blood is 6-8 hours in humans and 4-6 hours in rats 12,39 . Authors of previous publications, which investigated the effects Serelaxin on brain injury, either used a micro pump for continuous delivery of Serelaxin over a long period of time or evaluated the effects of the drug in short (4 hours) term studies [40][41][42][43] . In our preliminary experiments we figured out that P7 rat pups tolerate implantation of a mini pump rather badly.…”

Differential Expression of the Androgen Receptor, Splice Variants and Relaxin 2 in Renal Cancer

“…Renoprotective effects of relaxin, including attenuation of fibrosis, have been noted in patients with several diseases, such as dilated cardiomyopathy or age-related renal fibrosis [ 32 , 33 , 34 ]. In our cohort, relaxin expression was lower in tumors than in normal adjacent tissue.…”

“…RLN2 is a small, 6 kDa hormone that is involved in physiological and pathological conditions. Its activity during pregnancy and its involvement in several tumors have been widely described [ 27 , 28 , 29 , 30 , 31 , 32 ], although the role of RLN2 in RCC is not well understood.…”

“…The physiological expression of relaxin (and its receptor RXFP1) in the kidneys is not high. Even if its functional significance is still not clear, its protective activity has been suggested [ 32 ]. In particular, endogenous RLN2 is considered to serve as a renoprotective factor against fibrosis in the aging kidneys or after injury; however, this activity is sex-specific [ 33 , 34 ].…”