Pathogenesis of endothelial cell dysfunction in chronic kidney disease: a retrospective and what the future may hold

Abstract

Cardiovascular complications dominate the landscape of chronic kidney diseases (CKD). Endothelial cell dysfunction (ECD) is a well-known culprit of cardiovascular morbidity and it develops in CKD with remarkable frequency. This brief overview of ECD in CKD scans two decades of studies performed in my laboratory, from genetic analyses to proteomic and metabolomics screens. I provide a detailed description of findings related to the premature senescence of endothelial cells, cell transition from the endothelial to mesenchymal phenotype, and stages of development of ECD. Clinical utility of some of these findings is illustrated with data on laser-Doppler flowmetry and imaging in patients with CKD. Some currently available and emerging therapeutic options for the management of ECD are briefly presented.

Keywords: Endothelial-to-mesenchymal  transition; Metabolomics; Premature senescence proteomics; Stress-induced.

Figure 1

An “airport hub” model of endothelial functions. In this model, all functions are intrinsically interconnected, and any impairment of one would affect the others. Some essential mediators of these functions are shown in brackets. Pathophysiological consequences of endothelial dysfunction are depicted at the perimeter. EDHF, endothelium-derived hyperpolarizing factor; EDRF, endothelium-derived relaxing factor; HTN, hypertension; MCP, monocyte chemotactic protein; NO, nitric oxide; PA, plasminogen activator; PAI-1, plasminogen activator inhibitor-1; prot, protein; TF, tissue factor; VSM, vascular smooth muscle. Note. From “Endothelial cell dysfunction: can’t live with it, how to live without it,” by M.S. Goligorsky, 2005, Am J Physiol Renal Physiol, 288, p. F871. Copyright 2005, The American Physiological Society. Reprinted with permission.

Figure 2

Summary of homocysteine-induced molecular pathways predisposing to development of endothelial dysfunction. CYP, cytochrome P; ET-1, endothelin-1; EDHF, endothelium-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; HMGCoAR, 3-hydroxy-3methylglutaryl coenzyme A reductase; NCK, an adaptor protein; PECAM, CD31. Note. From “Endothelial cell dysfunction: can’t live with it, how to live without it,” by M.S. Goligorsky, 2005, Am J Physiol Renal Physiol, 288, p. F871. Copyright 2005, The American Physiological Society. Reprinted with permission.

Figure 3

Summary of asymmetric dimethylarginine-induced molecular pathways predisposing development of endothelial dysfunction.LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; SOD, superoxide dismutase. Note. From “Endothelial cell dysfunction: can’t live with it, how to live without it,” by M.S. Goligorsky, 2005, Am J Physiol Renal Physiol, 288, p. F871. Copyright 2005, The American Physiological Society. Reprinted with permission.

Figure 4

Summary of major functional and metabolomic findings and proposed pathways of l-glutamine (GLN) supplementation-induced amelioration of vascolopathy. See the text for details. eNOS, Endothelial nitric oxide synthase.