title: Cardiorenal fibrosis and dysfunction in aging: Imbalance in mediators and regulators of collagen.
abstract: Cardiorenal fibrosis is a biological process that increases with age and contributes to dysfunction of the heart and kidney. While numerous circulating and tissue hormones, cytokines and enzymes have been identified in the development of cardiorenal fibrosis, several reports have suggested that the anti-fibrotic natriuretic peptide system (NPS), pro-fibrotic renin-angiotensin-aldosterone system (RAAS), transforming growth factor-beta 1 (TGF-β1), matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) are fundamental regulators and mediators of this process. However, the simultaneous assessment of these components in the development of age-mediated cardiorenal fibrotic remodeling is not completely understood. Thus, we assessed cardiorenal structure and function, the circulating NPS and RAAS and the cardiorenal tissue gene expression of collagen (Col) I, Col III, TGF-β1, MMP-9 and TIMP-1 in 2 and 20 month old Fischer rats. Our studies determined that aging was characterized by an increase in cardiorenal fibrosis that was accompanied with cardiorenal dysfunction. These alterations were associated with lower circulating atrial and C-type natriuretic peptides and higher angiotensin II and aldosterone levels in the aged rats. Moreover, we observed a decrease in Col I and III and an increase in TIMP- mRNA expressions in the aged heart and kidney, while TGF-β1 expression increased and MMP-9 decreased only in the aged kidney. We conclude that the age-mediated alterations in these fibrotic regulator and mediator profiles favors collagen accumulation due to an imbalance between the NPS and RAAS as well as a decline in the degradative pathway, thus suggesting a therapeutic opportunity to target these components.
authors.affiliation: Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. Electronic address: sangaralingham.jeson@mayo.edu.
authors.forename: S Jeson
authors.initials: SJ
authors.lastname: Sangaralingham
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Bing H
authors.initials: BH
authors.lastname: Wang
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Sirinart
authors.initials: S
authors.lastname: Kumfu
authors.affiliation: Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichiki
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.affiliation: Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000375:Aging; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D004719:Endomyocardial Fibrosis / Q000378:metabolism*; D005355:Fibrosis; D015870:Gene Expression; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D045265:Natriuretic Peptides / Q000502:physiology; D011916:Rats, Inbred F344; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D045265:Natriuretic Peptides; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D003094:Collagen; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Cardiorenal; Fibrosis; Gene expression; Natriuretic peptides; Renin–angiotensin–aldosterone system