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, an increase in TIMP-1 and no change in MMP-9 mRNA expressions in the aged heart and kidney, while TGF-β1 expression increased 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.

The impacts of age and frailty on heart rate and sinoatrial node function

“…Our observations are also consistent with recent studies showing that ventricular fibrosis is increased in aged rats in association with changes in expression of MMPs and TIMPs rather than changes in collagen expression (Sangaralingham et al . , ) and with studies demonstrating that plasma levels of MMPs and TIMPs are altered in ageing humans (Bonnema et al . ).…”

Reproductive age-associated fibrosis in the stroma of the mammalian ovary

“…For these characterization studies, we used ovarian tissue from reproductively old mice (21-22 months old), as fibrosis increases with age in several tissues (Horn and Trafford 2015, Kapetanaki, et al 2013, Sangaralingham, et al 2016). We found a prominent network of intense PSR-stained collagen fibers throughout the ovarian stroma (Figure 1C).…”

“…In the lung, aging is associated with an increase of chronic lung diseases associated with fibrosis such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (Kapetanaki, et al 2013). In the aging kidney, glomerulosclerosis and interstitial fibrosis results in a decreased glomerular filtration rate (Denic, et al 2016, Sangaralingham, et al 2016). Whether fibrotic changes occur in the mammalian ovary, which ages up to decades prior to other organs in humans, has not been systematically investigated.…”

Tick-Tock Chimes the Kidney Clock – from Biology of Renal Ageing to Clinical Applications

“…Ageing also affects the endocrine function of the kidney. Despite decreased renin expression, angiotensin II activity increases with age [47, 48]. This may be due to increases in angiotensin II receptor sensitivity or differential regulation of systemic and intrarenal renin-angiotensin systems [49, 50].…”