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Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Galectin-3 (Gal-3) is a 30KDa lectin implicated in multiple pathophysiology pathways including renal damage and fibrosis. Gal-3 binds β-galactoside through its carbohydrate-recognition domain. From intra-cellular to extra-cellular localization, Gal-3 has multiple roles including transduction signal pathway, cell-to-cell adhesion, cell to extracellular matrix adhesion, and immunological chemoattractant protein. Moreover, Gal-3 has also been linked to kidney disease in both preclinical models and clinical studies. Gal-3 inhibition appears to improve renal disease in several pathological conditions, thus justifying the development of multiple drug inhibitors. This review aims to summarize the latest literature regarding Gal-3 in renal pathophysiology, from its role as a biomarker to its potential as a therapeutic agent.

De novo expression in the kidney of periostin, a protein involved in odontogenesis and osteogenesis, has been suggested as a biomarker of renal disease. In this study, we investigated the mechanism(s) of induction and the role of periostin in renal disease. Using a combination of bioinformatics, reporter assay, and chromatin immunoprecipitation analyses, we found that NF κ B and other proinflammatory transcription factors induce periostin expression in vitro and that binding of these factors on the periostin promoter is enriched in glomeruli during experimental GN. Mice lacking expression of periostin displayed preserved renal function and structure during GN. Furthermore, delayed administration of periostin antisense oligonucleotides in wild-type animals with GN reversed already established proteinuria, diminished tissue inflammation, and improved renal structure. Lack of periostin expression also blunted the de novo renal expression of integrin- β 3 and phosphorylation of focal adhesion kinase and AKT, known mediators of integrin- β 3 signaling that affect cell motility and survival, observed during GN in wild-type animals. In vitro , recombinant periostin increased the expression of integrin- β 3 and the concomitant phosphorylation of focal adhesion kinase and AKT in podocytes. Notably, periostin and integrin- β 3 were highly colocalized in biopsy specimens from patients with inflammatory GN. These results demonstrate that interplay between periostin and renal inflammation orchestrates inflammatory and fibrotic responses, driving podocyte damage through downstream activation of integrin- β 3 signaling. Targeting periostin may be a novel therapeutic strategy for treating CKD., (Copyright © 2017 by the American Society of Nephrology.)

The main hallmark of chronic kidney disease (CKD) is excessive inflammation leading to interstitial tissue fibrosis. It has been recently reported that NOV/CCN3 could be involved in kidney damage but its role in the progression of nephropathies is poorly known. NOV/CCN3 is a secreted multifunctional protein belonging to the CCN family involved in different physiological and pathological processes such as angiogenesis, inflammation and cancers. The purpose of our study was to determine the role of NOV/CCN3 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After unilateral ureteral obstruction (UUO), renal histology and real-time PCR were performed in NOV/CCN3-/- and wild type mice. NOV/CCN3 mRNA expression was increased in the obstructed kidneys in the early stages of the obstructive nephropathy. Interestingly, plasmatic levels of NOV/CCN3 were strongly induced after 7 days of UUO and the injection of recombinant NOV/CCN3 protein in healthy mice significantly increased CCL2 mRNA levels. Furthermore, after 7 days of UUO NOV/CCN3-/- mice displayed reduced proinflammatory cytokines and adhesion markers expression leading to restricted accumulation of interstitial monocytes, in comparison with their wild type littermates. Consequently, in NOV/CCN3-/- mice interstitial renal fibrosis was blunted after 15 days of UUO. In agreement with our experimental data, NOV/CCN3 expression was highly increased in biopsies of patients with tubulointerstitial nephritis. Thus, the inhibition of NOV/CCN3 may represent a novel target for the progression of renal diseases.

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.

Renal disease is a major public health challenge since its prevalence has continuously increased over the last decades. At the end stage, extrarenal replacement therapy and transplantation remain the only treatments currently available. To understand how the disease progresses, further knowledge of its pathophysiology is needed. For this purpose, experimental models, using mainly rodents, have been developed to unravel the mechanisms involved in the initiation and progression of renal disease, as well as to identify potential targets for therapy. The gap junction protein connexin 43 has recently been identified as a novel player in the development of kidney disease. Its expression has been found to be altered in many types of human renal pathologies, as well as in different animal models, contributing to the activation of inflammatory and fibrotic processes that lead to renal damage. Furthermore, Cx43 genetic, pharmacogenetic, or pharmacological inhibition preserved renal function and structure. This review summarizes the existing advances on the role of this protein in renal diseases, based mainly on different in vivo animal models of acute and chronic renal diseases. [ABSTRACT FROM AUTHOR]

The vasculature of the kidney is a heterogeneous structure, whose functional integrity is essential for the regulation of renal function. Owing to the importance of the endothelium in vascular biology, chronic endothelial alterations are therefore susceptible to impair multiple aspects of renal physiology and, in turn, to contribute to renal fibrosis. Although systemic endothelial dysfunction is undoubtedly associated with chronic kidney disease, the role of the renal endothelium in the initiation and the progression of renal fibrosis remains largely elusive. In this article, we critically review recent evidence supporting direct and indirect contributions of renal endothelial alterations to fibrosis in the kidney. Specifically, the potential implications of renal endothelial dysfunction and endothelial paucity in parenchymal hypoxia, in the regulation of local inflammation, and in the generation of renal mesenchymal cells are reviewed. We thereafter discuss therapeutic perspectives targeting renal endothelial alterations during the initiation and the progression of renal fibrogenesis. [ABSTRACT FROM AUTHOR]