Relaxin and castration in male mice protect from, but testosterone exacerbates, age-related cardiac and renal fibrosis, whereas estrogens are an independent determinant of organ size.
This study determined the effects of castration and hormone replacement therapy on the age-related cardiac and renal pathology of male relaxin gene-knockout (RlnKO) and age-matched wild-type (RlnWT) mice and that of aged male aromatase knockout (ArKO) mice, which lack estrogens and have 5-10 times the androgen levels of male wild-type mice. One-month-old RlnWT and RlnKO mice were bilaterally gonadectomized or sham operated and maintained until 12 months. Subgroups of castrated animals received testosterone or 17β-estradiol treatment from 9 to 12 months. Male ArKO mice and aromatase wild-type mice were aged to 12 months. Collected heart and kidney tissues were assessed for changes in organ size and fibrosis. Castration reduced body, heart, left ventricle, and kidney weights in both RlnKO and RlnWT mice, and the cardiac/renal fibrosis that was seen in sham RlnKO animals (all P < 0.05 vs. respective sham). Testosterone normalized organ weights and organ weight to body weight ratio of castrated animals and increased cardiac/renal collagen concentration to levels measured in or beyond that of sham RlnKO mice (all P < 0.05 vs. respective castrated mice). Furthermore, expression of TGF-β1, mothers against decapentaplegic homolog 2 (Smad2), and myofibroblast differentiation paralleled the above changes (all P < 0.05 vs. respective castrated mice), whereas matrix metalloproteinase-13 was decreased in testosterone-treated RlnKO mice. Conversely, 17β-estradiol only restored changes in organ size. Consistent with these findings, intact ArKO mice demonstrated increased cardiac/renal fibrosis in the absence of changes in organ size. These findings suggest that relaxin and castration protect, whereas androgens exacerbate, cardiac and renal fibrosis during ageing, whereas estrogens, in synergy with relaxin, regulates age-related changes in organ size.
Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
Tim D
TD
Hewitson
Chongxin
C
Zhao
Belinda
B
Wigg
Sin Wai
SW
Lee
Evan R
ER
Simpson
Wah Chin
WC
Boon
Chrishan S
CS
Samuel
D000199:Actins / Q000378:metabolism; D000375:Aging / Q000473:pathology; D000818:Animals; D001141:Aromatase / Q000172:deficiency / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage*; D005355:Fibrosis; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism; D012065:Relaxin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D013739:Testosterone / Q000008:administration & dosage*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000199:Actins; D011944:Receptors, Androgen; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D013739:Testosterone; D004958:Estradiol; D012065:Relaxin; D003094:Collagen; D001141:Aromatase; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse