Human recombinant relaxin-2 does not attenuate hypertension or renal injury but exacerbates vascular dysfunction in a female mouse model of SLE

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects women of reproductive age and increases their risk for developing hypertension, vascular, and renal disease. Relaxin has potential beneficial therapeutic effects in cardiovascular disease through direct actions on the vasculature. The potential therapeutic benefit of relaxin on SLE-associated cardiovascular and renal risk factors like hypertension has not previously been tested. We hypothesized that relaxin would attenuate hypertension, renal injury, and vascular dysfunction in an established female mouse model of SLE (NZBWF1 mice). Serelaxin (human recombinant relaxin-2, 0.5 mg·kg−1·day−1) or vehicle was administered via osmotic mini-pump for 4 wk in female control (NZW) or SLE mice between 28 and 31 wk of age. Serelaxin treatment increased uterine weights in both groups, suggesting that the Serelaxin was bioactive. Mean arterial pressure, measured by carotid artery catheter, was significantly increased in vehicle-treated SLE mice compared with vehicle-treated controls, but was not changed by Serelaxin treatment. Albumin excretion rate, measured by ELISA, was similar between vehicle- and Serelaxin-treated SLE mice and between vehicle- and Serelaxin-treated control mice. Wire myography was performed using isolated carotid arteries to assess endothelial-independent and -dependent vasodilation, and data confirm that SLE mice have impaired endothelium-independent and -dependent relaxation compared with control mice. Serelaxin treatment did not affect endothelium-independent vasodilation, but exacerbated the endothelium-dependent dysfunction. These data suggest that, contrary to our hypothesis, Serelaxin infusion does not attenuate hypertension, renal injury, or vascular dysfunction in SLE, but worsens underlying vascular endothelial dysfunction in this experimental model of SLE. These data do not support the use of human recombinant relaxin-2 as an antihypertensive in the SLE patient population. NEW & NOTEWORTHY Relaxin is a peptide hormone commonly known for its role in pregnancy and for its use in recent clinical trials for the treatment of heart failure. Evidence suggests that relaxin has immunomodulatory effects; however, the potential therapeutic impact of relaxin in chronic immune mediated disease is unclear. This study tests whether recombinant human relaxin (Serelaxin) attenuates the progression of autoimmunity, and the associated cardiovascular consequences, in an experimental model of systemic lupus erythematosus.

Identification of hub ferroptosis-related genes and immune infiltration in lupus nephritis using bioinformatics

“…Since autophagy is essential in maintaining renal cell metabolism and organelle homeostasis, upregulation of autophagic activity may play a role in lupus nephritis to protect and limit kidney injury 28 . Due to the antifibrotic effect of relaxin in an experimental model of chronic kidney disease, it is hypothesized that relaxin may be able to improve the progression of LN 29 , 30 . VEGF has been shown to be a marker of disease activity in SLE and LN 31 .…”

Vascular Inflammation in Mouse Models of Systemic Lupus Erythematosus

“…Some strains including MRL/Fas lpr , BXSB, and (NZW/BXSB) F1, may also develop myocardial infarctions ( 55 ). NZB/NZW F1 mice and some induced models develop hypertension, which may be used as another measure of CVD progression ( 23 , 25 , 27 , 32 – 36 , 44 ).…”

“…The exact pathogenesis of hypertension in human SLE is not well-understood, but is thought to be related to some combination of endothelial dysfunction, kidney damage, abnormalities in the renin-angiotensin-aldosterone system, dysautonomia, and increased endothelin-1 ( 17 ). The degree of hypertension in mice may be measured by tail cuff for systolic blood pressure ( 33 , 34 ) or by catheterization for mean arterial pressure ( 35 , 36 ). The main mouse models generally used to study SLE hypertension are pristane-induced models and the NZB/NZW F1 strain.…”