Remodeling In Kidney Disease Research Articles

Correction to: GDP in Dialysis Associates with Peritoneal Vascular Remodeling in Kidney Disease.

Correction to: GDP in Dialysis Associates with Peritoneal Vascular Remodeling in Kidney Disease.

The Pivotal Role of Oxidative Stress in the Pathophysiology of Cardiovascular-Renal Remodeling in Kidney Disease.

The excessive activation of the renin-angiotensin system in kidney disease leads to alteration of intracellular pathways which concur altogether to the induction of cardiovascular and renal remodeling, exposing these patients since the very beginning of the renal injury to chronic kidney disease and progression to end stage renal disease, a very harmful and life threatening clinical condition. Oxidative stress plays a pivotal role in the pathophysiology of renal injury and cardiovascular-renal remodeling, the long-term consequence of its effect. This review will examine the role of oxidative stress in the most significant pathways involved in cardiovascular and renal remodeling with a focus on the detrimental effects of oxidative stress-mediated renal abnormalities on the progression of the disease and of its complications. Food for thoughts on possible therapeutic target are proposed on the basis of experimental evidences.

Increased Levels of sRAGE in Diabetic CKD-G5D Patients: A Potential Protective Mechanism against AGE-Related Upregulation of Fibroblast Growth Factor 23 and Inflammation.

Advanced glycation end products (AGEs) may induce cardiac remodeling in kidney disease by promoting fibroblast growth factor 23 (FGF-23) expression. Since AGEs are increased in diabetes mellitus (DM), our first aim was to evaluate the existence of any potential association between AGEs, FGF-23, inflammation, and increased cardiovascular risk in DM patients on dialysis (CKD-G5D). Secondarily, we explored the potential role of the soluble receptor for AGEs (sRAGE) as a marker of heart failure. Levels of glycated albumin (GA), sRAGE, c-terminal FGF-23 (cFGF-23), brain natriuretic peptide (BNP), and inflammatory mediators were compared between DM and non-DM CKD-G5D patients. The levels of sRAGE, cFGF-23, BNP, and proinflammatory markers were over the ranges of normality in both DM and non-DM groups. Only GA and sRAGE levels were increased in DM compared to non-DM patients. Plasma levels of sRAGE and CRP were the only independent predictors of BNP concentration. In conclusion, in DM CKD-G5D patients, sRAGE appeared to be a marker of cardiac remodeling. Indeed, its increase could be a potential protective mechanism against the increased risk of cardiovascular complications related to AGEs and inflammation. The causal relationship between sRAGE and cardiovascular risk in these patients needs to be further confirmed by mechanistic studies.

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis.

Transient receptor potential canonical (TRPC) Ca(2+)-permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca(2+) entry in these cells, which was detected by fura-2 Ca(2+) imaging. TRPC3 blockade or Ca(2+) removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca(2+) entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca(2+)-mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.

NOD-like and Toll-like receptors or inflammasomes contribute to kidney disease in a canonical and a non-canonical manner

Tissue remodeling in kidney disease involves sterile inflammation, because tissue necrosis, in acute kidney injury, produces endogenous agonists to innate pattern recognition receptors that trigger innate immunity. In chronic kidney disease, however, a functional role of such pattern recognition receptors is questionable. Here we summarize and discuss the current evidence on a potential contribution of canonical and non-canonical pattern recognition receptor signaling in chronic kidney disease.

Integrins in Kidney Disease

A major hallmark of chronic kidney injury is fibrosis, which is characterized by increased accumulation of extracellular matrix components that replace the damaged tissue. Normally, the synthesis and degradation of extracellular matrix components are finely regulated; however, when matrix replacement goes unchecked, there is unwanted and irreversible tissue scarring with consequent organ damage, organ failure, and, in certain cases, death. Many factors, including cell-matrix interactions, play a role in the development of renal fibrosis. Cell-matrix interactions are made possible by integrins, a family of transmembrane receptors that, upon binding to the extracellular matrix, activate intracellular signaling. Thus, they control various cell functions, including survival, proliferation, migration, and matrix homeostasis. Genetic mutations in humans and the development of animal models lacking integrins in selective parts of the kidney have improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in kidney disease. Here we outline the major integrins involved in kidney disease and some of the major molecular mechanisms whereby integrins contribute to kidney fibrosis.