Relaxin ameliorates salt-sensitive hypertension and renal fibrosis

Yoshida, Takuya; Kumagai, Hiromichi; Suzuki, Ayumi; Kobayashi, Noboru; Ohkawa, Sakae; Odamaki, Mari; Kohsaka, Tetsuya; Yamamoto, Tatsuo; Ikegaya, Naoki

doi:10.1093/ndt/gfr618

Cited by 34 publications

(44 citation statements)

References 40 publications

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“…RLX may protect preservation of tubular cells and these functions by anti-apoptotic effects. Previously, we demonstrated that RXFP1 and nNOS were localized to distal tubular epithelial cells in the rats [8]. In this study, CDDP induced renal tubular injury and decreased RXFP1 and nNOS mRNA expression, whereas RLX attenuated the decrease of RXFP1 and nNOS mRNA expression by CDDP.…”

Section: Discussionsupporting

confidence: 47%

“…In the short-term experiments, the paraffin-embedded kidney sections (3 μm) were stained using the periodic acid-Schiff (PAS) method. Tubular epithelial damage was evaluated using a semiquantitative grading system as described previously [8]. …”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed by using the Dako EnVision-HRP Detection Kit (Dako, Kyoto, Japan) as described in detail previously [8]. The primary antibodies were as follows: thrombomodulin antibody (kindly provided by Dr. M. Nakano, Mitsubishi Gas Chemical Co. Inc., Niigata, Japan), RLX receptor (RXFP1) [14].…”

Section: Methodsmentioning

confidence: 99%

“…One of the important roles of RLX is its anti-fibrotic effect, which is known to prevent exacerbations of various diseases, including the heart [6], lungs [7], and kidneys [8]. Furthermore, RLX has gained attention because of its anti-apoptotic and anti-inflammatory properties in various tissues [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Relaxin against Cisplatin-Induced Nephrotoxicity in Rats

Yoshida

Kumagai

Kohsaka

et al. 2014

Nephron Exp Nephrol

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Background: Cisplatin (CDDP)-induced acute kidney injury (AKI) involves pro-inflammatory responses, apoptosis of renal tubular epithelial cells and vascular damage. AKI increases the risk of chronic kidney disease. Relaxin (RLX) has anti-apoptotic and anti-fibrosis properties. The aim of this study was to investigate the effects of RLX on CDDP-induced nephrotoxicity. Methods: We investigated the mitigating effects of RLX based on the etiopathology of AKI induced by CDDP, and also the anti-fibrotic effect of RLX on renal fibrosis after AKI. In the short-term experiments, rats were divided into the control group, CDDP group, and CDDP+RLX group. In the latter group, RLX was infused for 5 or 14 days using an implanted osmotic minipump. CDDP was injected intraperitoneally (6 mg/kg) after RLX or saline infusion. At 5 and 14 days post-CDDP, the kidneys were removed for analysis. The effect of RLX on renal fibrosis after AKI was evaluated at 6 weeks post-CDDP. Results: In short-term experiments, CDDP transiently increased plasma creatinine and blood urea nitrogen with peaks at day 5, and RLX prevented such rises. Semiquantitative analysis of the histological lesions indicated marked structural damage and apoptotic cells in the CDDP group, with the lesions being reduced by RLX treatment. Overexpression of Bax, interleukin-6 and tumor necrosis factor-α observed in the kidneys of the CDDP group was reduced in the CDDP+RLX group. In the long-term experiments, RLX significantly reduced renal fibrosis compared with the CDDP group. Conclusions: The results suggested that RLX provided protection against CDDP-induced AKI and subsequent fibrosis by reducing apoptosis and inflammation.

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Section: Discussionsupporting

confidence: 47%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Relaxin against Cisplatin-Induced Nephrotoxicity in Rats

Yoshida

Kumagai

Kohsaka

et al. 2014

Nephron Exp Nephrol

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“…Combining Dahl salt-sensitive hypertensive with Dahl saltresistant normotensive rats, researchers in Japan have found that when treated with H2 relaxin after six weeks, 34) DS rats' systolic blood pressure decreased significantly, glomerular and tubular fibrosis lesions were alleviated and TGF-β signal transduction decreased. In another study, 35) administration of H2 relaxin to rats with the anti-thymocyte serum nephritis model resulted in a decrease of PAS staining positive matrix, SMAD2 phosphorylation and mesangial cell proliferation while α-SMA expression were found.…”

Section: Discussionmentioning

confidence: 99%

Relaxin Inhibits High Glucose-Induced Matrix Accumulation in Human Mesangial Cells by Interfering with TGF-β1 Production and Mesangial Cells Phenotypic Transition

Xie

Xia

Xiao

et al. 2015

Biological & Pharmaceutical Bulletin

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). DN is characterizedby glomerular extracellular matrix accumulation, mesangial expansion, basement membrane thickening, and renal interstitial fibrosis. To date, mounting evidence has shown that H2 relaxin possesses powerful antifibrosis properties; however, the mechanisms of H2 relaxin on diabetic nephropathy remain unknown. Here, we aimed to explore whether H2 relaxin can reduce production of extracellular matrix (ECM) secreted by human mesangial cells (HMC). HMC were exposed to 5.5 mM glucose (NG) or 30 mM glucose (HG) with or without H2 relaxin. Fibronectin (FN) and collagen type IV levels in the culture supernatants were examined by solid-phase enzyme-linked immunoadsorbent assay (ELISA). Western blot was used to detect the expression of α-smooth muscle actin (α-SMA) protein. Quantitative polymerase chain reaction (qPCR) method was employed to analyze transforming growth factor (TGF)-β1 mRNA expression. Compared with the normal glucose group, the levels of fibronectin and collagen type were markedly increased after being cultured in high glucose medium. Compared with the high glucose group, remarkable decreases of fibronectin, collagen type IV, α-smooth muscle actin, and TGF-β1 mRNA expression were observed in the H2 relaxin-treated group. The mechanism by which H2 relaxin reduced high glucose-induced overproduction of ECM may be associated with inhibition of TGF-β1 mRNA expression and mesangial cells' phenotypic transition. H2 relaxin is a potentially effective modality for the treatment of DN.Key words human mesangial cell (HMC); human H2 relaxin; extracellular matrix (ECM); transforming growth factor (TGF)-β1; diabetic nephropathy (DN) Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes, and a major cause of end-stage renal disease (ESRD).1) Once the clinical diabetic nephropathy is diagnosed, most of the DN patients will inevitably develop ESRD after several years due to the lack of effective methods to delay its progression.2) Its pathology is characterized by glomerular extracellular matrix accumulation, mesangial expansion, basement membrane thickening, glomerulosclerosis and renal interstitial fibrosis.3) Laminin, fibronectin and type IV collagen are the main components of extracellular matrix, and the excessive extracellular matrix (ECM) plays a key role in the progression of diabetic nephropathy. 4)Previous in vitro studies 5,6) revealed that high glucose can stimulate the synthesis of ECM including fibronectin and type IV collagen through the activation of the transforming growth factor (TGF)-β dependent Smad signaling pathway, as well as upregulation of its receptor expression. Recently Liu et al. 7) reported that both 30 mM glucose (HG) and TGF-β1 can lead to over production of fibronectin. The underlying mechanism was thought to be mesangial cell caveolae has a role in regulating fibronectin production partly through caveolin-1 phosphorylation.TGF-β is recognized as a major mediat...

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Relaxin: New Pathophysiological Aspects and Pharmacological Perspectives for an Old Protein

Cernaro

Lacquaniti

Lupica

et al. 2013

Medicinal Research Reviews

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Human relaxin-2 (hereafter simply defined as "relaxin") is a 6-kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in-depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future.

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Relaxin ameliorates salt-sensitive hypertension and renal fibrosis

Abstract: The results suggested that RLX converted salt sensitivity to salt resistance, at least in part, by up-regulating NOS. RLX is a potentially useful therapeutic agent for salt-sensitive hypertension.

Cited by 34 publications

References 40 publications

Protective Effects of Relaxin against Cisplatin-Induced Nephrotoxicity in Rats

Protective Effects of Relaxin against Cisplatin-Induced Nephrotoxicity in Rats

Relaxin Inhibits High Glucose-Induced Matrix Accumulation in Human Mesangial Cells by Interfering with TGF-β1 Production and Mesangial Cells Phenotypic Transition

Relaxin: New Pathophysiological Aspects and Pharmacological Perspectives for an Old Protein

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