The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

Abstract

: Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.

Keywords: CKD; MMPs; PAD.; TIMPs; biomarkers; eGFR; metalloproteinases; peripheral vascular disease; proteinuria.

Figure 1

Expression of MMPs and TIMPs, and pathophysiological mechanisms of vascular and kidney damage [10,11,27,28,29,30,31]. EMT, epithelial-mesenchymal transition; VSMC, vascular smooth muscle cells; TGF-β, transforming growth factor-β.

Figure 2

Prevalence of cardiovascular diseases according to the presence (dark blue bars) or absence (turquoise bars) of Chronic Kidney Disease (CKD) in the United States, in the year 2015. AF, atrial fibrillation; AMI, acute myocardial infarction; CAD, coronary artery disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; HF, heart failure; PAD, peripheral arterial disease.