Alteration of connexin expression is an early signal for chronic kidney disease

Abstract

Chronic kidney disease is promoted by a variety of factors that induce chronic inflammation and fibrosis. Inflammation and excessive scaring have been recently associated with disruptions of the gap junction-mediated intercellular communication. Nevertheless, little is known about alterations of the expression of gap junction proteins such as connexin (Cx) 43 and 37 in chronic renal disease. In this study, we investigated the expression of these two Cxs in the hypertensive RenTg mice, the anti-glomerular basement membrane glomerulonephritis, and the unilateral ureteral obstruction models, all leading to the development of chronic kidney disease in mice. Expression of Cx43 was almost negligible in the renal cortex of control mice. In contrast, Cx43 was markedly increased in the endothelium of peritubular and glomerular capillaries of the 3-mo-old RenTg mice, in the glomeruli of mice suffering from glomerulonephritis, and in the tubules after obstructive nephropathy. The Cx43 expression pattern was paralleled closely by that of the adhesion markers such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 as well as the inflammatory biomarker monocyte chemoattractant protein-1. In contrast, Cx37 that was abundantly expressed in the renal cortex of healthy mice was markedly decreased in the three experimental models. Interestingly, Cx43+/- mice showed restricted expression of VCAM-1 after 2 wk of obstructive nephropathy. These findings suggest the importance of Cxs as markers of chronic renal disease and indicate that these proteins may participate in the inflammatory process during the development of this pathology.

Gene Expression Analysis and Urinary Biomarker Assays Reveal Activation of Tubulointerstitial Injury Pathways in a Rodent Model of Chronic Proteinuria (Doxorubicin Nephropathy)

“…Table 2 lists the 53 transcripts that have been previously reported to play a role in ischemia-reperfusion (IR), nephrotoxicity, or proteinuria [4,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45], suggesting a striking overlap in the kidney's transcriptional responses to a wide variety of insults. In the tubules, there was upregulation of many cell cycle, cell stress, apoptosis and inflammatory genes with concurrent downregulation of membrane transporters.…”

Low pH enhances connexin32 degradation in the pancreatic acinar cell

“…This newly described pathway may be relevant to other tissues and disease processes. Thus metabolic acidosis increases the severity or the risk of a number of other diseases, including cardiac arrhythmias, osteoporosis, and chronic kidney disease, which also involve perturbed gap junction function/structure (11,18,21,30,34,43).…”

Connexin 43: a New Therapeutic Target Against Chronic Kidney Disease

“…In 2011, our group published a study on the expression of Cx43 in different models of CKD. Among other findings, we showed that in the model of nephrotoxic serum-induced glomerulonephritis (NTS-GN) in mice, Cx43 was strongly upregulated in suffering glomeruli [44]. A year later, an in vitro study on murine podocytes exposed to PAN pointed towards a deleterious role of Cx43 in injured podocytes [54].…”

“…To study expression and localization of Cx43 in a model of tubular disease in vivo, we used the well-established model of unilateral ureteral obstructive nephropathy (UUO) in mice [44]. Cx43 was barely detected in control tubular cells but after UUO it was strongly expressed in tubules of both cortex and medulla.…”