Extracellular matrix roles in cardiorenal fibrosis: Potential therapeutic targets for CVD and CKD in the elderly

Abstract

Whereas hypertension, diabetes, and dyslipidemia are age-related risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), aging alone is an independent risk factor. With advancing age, the heart and kidney gradually but significantly undergo inflammation and subsequent fibrosis, which eventually results in an irreversible decline in organ physiology. Through cardiorenal network interactions, cardiac dysfunction leads to and responds to renal injury, and both facilitate aging effects. Thus, a comprehensive strategy is needed to evaluate the cardiorenal aging network. Common hallmarks shared across systems include extracellular matrix (ECM) accumulation, along with upregulation of matrix metalloproteinases (MMPs) including MMP-9. The wide range of MMP-9 substrates, including ECM components and inflammatory cytokines, implicates MMP-9 in a variety of pathological and age-related processes. In particular, there is strong evidence that inflammatory cell-derived MMP-9 exacerbates cardiorenal aging. This review explores the potential therapeutic targets against CVD and CKD in the elderly, focusing on ECM and MMP roles.

Keywords: Cardiorenal aging; Extracellular matrix; Fibrosis; Inflammaging; Matrix metalloproteinase-9.

Fig. 1.

Mechanisms of cardiorenal interaction, showing the association among cardiac, renal and vascular dysfunction. While aging itself and common diseases such as hypertension, diabetes, and dyslipidemia are important risk factors for cardiovascular disease and chronic kidney disease, cardiac, renal, and vascular dysfunction exacerbate each other. Hatched lines show physiological interactions, and solid lines indicate the adverse interactions among organs.

Fig. 2.

Mechanistic figure showing the development process of inflammation and fibrosis in the aging left ventricle (LV). Age-related LV wall thickness and myocyte hypertrophy generate an additional oxygen demand, which in turn increases the production of angiogenic stimuli. Despite the production of angiogenic stimuli, blood vessel numbers do not increase in aging LV. Together with nitric oxide deficiency due to endothelial cell senescence, vessel rarefaction leads to an hypoxic state, which triggers inflammation and subsequent fibrosis.

Fig. 3.

Mechanistic diagram showing effects of macrophage-derived matrix metalloproteinase (MMP)-9 in cardiorenal aging. In addition to reported common aging mechanisms such as oxidative stress, renin-angiotensin system (RAS), nitric oxide (NO) deficiency, and advanced glycation end product (AGE), all of which cause cellular senescence, and extracellular matrix (ECM) components including osteopontin and secreted protein acidic and rich in cysteine (SPARC), macrophage-derived MMP-9 causes inflammation and fibrosis dependent and independent vascular rarefaction in the heart and kidney. Age-related systemic changes and comorbidities of risk factors (hypertension, diabetes, dyslipidemia) facilitates cardiorenal aging. Cardiovascular disease (CVD) and chronic kidney disease (CKD) interact each other, exacerbating their dysfunctional changes.

Fig. 4.

Suggested roles of matrix metalloproteinase (MMP)-9 in inflammaging and fibrosis in the heart and the kidney. MMP-9, produced from recruited macrophages in the aging heart, promotes inflammaging by increasing macrophage M1 polarization, not macrophage recruitment. Macrophage-derived MMP-9 in the aging kidney induces both macrophage M1 polarization and leucocyte mobilization. MMP-9 converts latent TGF-β to active form, which leads to fibrosis. Epithelial-mesenchymal transition (EMT) in the kidney is both TGF-β-dependent and independent. EndMT; endothelial-to-mesenchymal transition.