Disease relevance of Rln1

• Rln1-knockout mice show progressive tissue fibrosis as they age, and this fibrosis leads to functional changes in both the heart and lungs [1].
• Rln1 knockout mice exhibit abnormal nipple development, prolonged parturition, agerelated pulmonary fibrosis, and abnormalities in the testes and prostate [2].
• Functional expression of mouse relaxin and mouse relaxin-3 in the lung from an Ebola virus glycoprotein-pseudotyped lentivirus via tracheal delivery [3].
• Studies in RLX-deficient mice (Rlx-/-) demonstrate that although females give birth to live young without apparent dystocia, the pubic symphysis is not elongated, and they have abnormal cervical and vaginal morphology [4].
• Cardiac hypertrophy, evidenced by increased heart weight and expression of hypertrophy-related genes (all P < 0.05 vs. sham) was only observed in Rln1-/- mice [5].
• The model of AAD was applied to 12-month-old relaxin-deficient (Rln(-/-)) mice with established airway fibrosis and age-matched wild-type (Rln(+/+)) controls [6].
• Collectively, the extent of pressure overload-induced LV hypertrophy, fibrosis, and dysfunction were comparable between Rln1+/+ and Rln1-/- mice [7].

High impact information on Rln1

• Reconstitution of reproductive functions in the ob/ob female necessitates delivery of hypothalamic extracts to the third ventricle (8) and administration of pituitary extract (9), gonadotropic hormones (10), progesterone (11) and relaxin (12) [8].
• Relaxin has been reported to reduce fibrosis in the kidney, heart, lung, and liver and to promote wound healing [9].
• Relaxin promotes growth and softening of the cervix, thus facilitating rapid delivery of live young [9].
• Whereas relaxin is required for development of the mammary nipples in rats and mice, it is essential for prepartum development of glandular parenchyma in pregnant pigs [9].
• Finally, relaxin counteracts allergic reactions [9].

Chemical compound and disease context of Rln1

• The increased collagen expression in the kidney was associated with increased glomerular matrix and to a lesser extent, interstitial fibrosis in RLX-/- mice, which also had significantly increased serum creatinine (P < 0.05) and urinary protein (P < 0.05) [10].
• In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo [11].
• The effects of relaxin and estrogen deficiency on collagen deposition and hypertrophy of nonreproductive organs [5].
• Moreover, uterine strips from estrogenized mice were placed in an organ bath, and the effect of relaxin on K+-induced contracture was evaluated in the presence or absence of the NOS inhibitor nitro-L-arginine [12].
• In adult rat cardiomyocytes, relaxin blunted phenylephrine-induced hypertrophy by inhibiting activated ERK-1/2 kinases [13].

Biological context of Rln1

• Double mutant males have normal-sized prostate and testes, suggesting that Lgr8 does not account for differences in Rln1-/- and Lgr7-/- phenotypes [2].
• There was a significant (P < 0.05) decrease in myometrial LGR7 gene expression on d 17.5 and 18.5 post coitum (pc) compared with earlier stages of gestation, but no differences between Rlx+/+ and Rlx-/- mice [14].
• ERalpha gene expression was up-regulated on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation [14].
• Relaxin decreases oxytocin-stimulated rat myometrial contractions in vitro [15].
• (Burkhardt, E., Adham, I. M., Brosig, B., Gastmann, A., Mattei, M. G., and Engel, W. (1994) Genomics 20, 13-19) Leydig cells contain the message for a protein of the insulin/relaxin family which was named Leydig cell insulin-like protein (LEY I-L) [16].

Anatomical context of Rln1

• We also characterized the temporal expression of the RLX receptor (LGR7) and demonstrated gene transcripts in the myometrium of Rlx+/+ and Rlx-/- mice [14].
• Endocrine effects of relaxin overexpression in mice [17].
• The current study examined phenotypic differences in collagen, matrix metalloproteinases (MMP), and estrogen receptors (ERs) in the cervix and vagina of pregnant Rlx+/+ and Rlx-/- mice [4].
• Ovariectomy of Rln1+/+ mice also led to a significant increase in airway smooth muscle (SM) (lung) thickening, which was further exaggerated in Rln1-/- mice [5].
• These coherent findings indicate that relaxin regulates fibroblast proliferation, differentiation, and collagen deposition and may have therapeutic potential in diseased states characterized by cardiac fibrosis [18].

Associations of Rln1 with chemical compounds

• Both genes encode a putative prohormone sequence incorporating the classic two-chain, three cysteine-bonded structure of the relaxin/insulin family and, importantly, contain the RXXXRXX(I/V) motif in the B-chain that is essential for relaxin receptor binding [19].
• Heterozygous (rlx+/-) mice lactate normally [20].
• As proliferation and differentiation of uterine and vaginal epithelia are thought to be induced by a paracrine stromal factor that acts upon estrogen stimulation, our results indicate that relaxin may be this paracrine factor [21].
• Vaginal and cervical luminal epithelia, which proliferated markedly in the rlx +/+ pregnant mice, remained relatively atrophic in the rlx -/- mice [21].
• Relaxin is a 6 kDa protein hormone produced by the corpus luteum and secreted into the blood during pregnancy in rodents and humans [22].

Regulatory relationships of Rln1

• Relaxin is known to promote uterine quiescence [12].
• Cardiomyocytes and relaxin upregulated connexin43 expression and gap junctional communication in myoblasts [23].

Other interactions of Rln1

• The effects of RLX on OTRs are probably mediated via activation of ERalpha [14].
• However, Lgr7-deficient males do not exhibit abnormalities in the testes or prostate as seen in Rln1 knockout mice [2].
• Myometrial OTR mRNA levels increased at the end of gestation in Rlx+/+ but not Rlx-/- mice [14].
• The expression of relaxin was detected in the pancreas of the transgenic animals [17].
• There was also a significant reduction in ERbeta expression in RLX-treated Rlx-/- mice [4].

Analytical, diagnostic and therapeutic context of Rln1

• ERT significantly decreased airway fibrosis, airway SM thickening, and cardiac hypertrophy when administered to ovariectomized Rln1-/- mice (all P < 0.05 vs. ovariectomy alone) [5].
• The expression of this novel relaxin gene was studied in mouse tissues using RT-PCR, where transcripts were identified with a pattern of expression distinct from that of the previously characterized mouse relaxin [19].
• These data, together with the localization of transcripts in the pars ventromedialis of the dorsal tegmental nucleus of C57BLK6J mouse brain by in situ hybridization histochemistry, suggest a new role for relaxin in neuropeptide signaling processes [19].
• We have used gene targeting to generate relaxin (rlx)-deficient mice [20].
• Sequence analysis in combination with mass spectrometry and tryptic peptide mapping showed unambiguously that RLF is larger than previously assumed and that it has the relaxin-type disulfide bond distribution that makes it a bona fide member of the relaxin family of hormones [24].

References