title: Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy?
abstract: A recurring theme of a host of gerontologic studies conducted in either experimental animals or in humans is related to documenting the functional decline with age. We hypothesize that elevated circulating levels of a powerful antiangiogenic peptide, endostatin, represent one of the potent systemic causes for multiorgan microvascular rarefaction and functional decline due to fibrosis. It is possible that during the life span of an organism there is an accumulation of dormant transformed cells producing antiangiogenic substances (endostatin) that maintain the dormancy of such scattered malignant cells. The proof of this postulate cannot be obtained by physically documenting these scattered cells, and it rests exclusively on the detection of sequelae of shifted pro- and antiangiogenic balance toward the latter. Here we compared circulating levels of endostatin in young and aging mice of two different strains and showed that endostatin levels are elevated in the latter. Renal expression of endostatin increased ~5.6-fold in aging animals. This was associated with microvascular rarefaction and progressive tubulointerstitial fibrosis. In parallel, the levels of sirtuins 1 and 3 were significantly suppressed in aging mice in conjunction with the expression of markers of senescence. Treating young mice with endostatin for 28 days showed delayed recovery of circulation after femoral artery ligation and reduced patency of renal microvasculature but no fibrosis. In conclusion, the findings are consistent with the hypothesis on elevation of endostatin levels and parallel microvascular rarefaction and induction of renal fibrosis in aging mice.
authors.affiliation: Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York.
authors.forename: Chi Hua Sarah
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Cardiovascular Science, National Institutes of Health, National Institute on Aging, Baltimore, Maryland;
authors.forename: Bruce
authors.initials: B
authors.lastname: Ziman
authors.affiliation: Laboratory of Cardiovascular Science, National Institutes of Health, National Institute on Aging, Baltimore, Maryland;
authors.forename: Shannon
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Department of Intensive Care Medicine, University of Amiens, Amiens, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.affiliation: Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York, michael_goligorsky@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D000375:Aging / Q000097:blood* / Q000473:pathology*; D000818:Animals; D043169:Endostatins / Q000097:blood* / Q000235:genetics; D005355:Fibrosis; D058685:Genetic Pleiotropy; D007668:Kidney / Q000098:blood supply* / Q000473:pathology*; D051379:Mice; D055806:Microvessels / Q000502:physiology; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D056564:Sirtuin 1 / Q000097:blood; D056566:Sirtuin 3 / Q000097:blood
chemical_list: D043169:Endostatins; D056564:Sirtuin 1; D056566:Sirtuin 3
keywords: aging; antiangiogenesis; dormant tumors; endostatin
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