Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice.

Excessive recruitment of monocytes and progression of fibrosis are hallmarks of chronic kidney disease (CKD). Recently we reported that the expression of connexin 43 (Cx43) was upregulated in the kidney during experimental nephropathy. To investigate the role of Cx43 in the progression of CKD, we interbred RenTg mice, a genetic model of hypertension-induced CKD, with Cx43+/- mice. The renal cortex of 5-month-old RenTgCx43+/- mice showed a marked decrease of cell adhesion markers leading to reduced monocyte infiltration and interstitial renal fibrosis compared with their littermates. In addition, functional and histological parameters such as albuminuria and glomerulosclerosis were ameliorated in RenTgCx43+/- mice. Interestingly, treatment with Cx43 antisense produced remarkable improvement of renal function and structure in 1-year-old RenTg mice. Similar results were found in Cx43+/- or wild-type mice treated with Cx43 antisense after obstructive nephropathy. Furthermore, in these mice, Cx43 antisense attenuated E-cadherin downregulation and phosphorylation of the transcription factor Sp1 by the ERK pathway resulting in decreased transcription of type I collagen gene. Interestingly, Cx43-specific blocking peptide inhibited monocyte adhesion in activated endothelium and profibrotic pathways in tubular cells. Cx43 was highly increased in biopsies of patients with CKD. Thus, Cx43 may represent a new therapeutic target against the progression of CKD.

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

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.

The RenTg mice: a powerful tool to study renin-dependent chronic kidney disease.

BACKGROUND: Several studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD. METHODOLOGY/PRINCIPAL FINDINGS: We used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFß family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation. CONCLUSIONS/SIGNIFICANCE: The RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease.