Interactions between Angiotensin II and NF-κB–Dependent Pathways in Modulating Macrophage Infiltration in Experimental Diabetic Nephropathy

Abstract

Abstract. NF-B-dependent pathways play an important role in macrophage infiltration and kidney injury. NF-B is regulated by angiotensin II (AII). However, the role of this pathway in diabetic nephropathy has not been clearly delineated. First, the activation of NF-B, monocyte chemoattractant protein-1 (MCP-1), and macrophage infiltration in the diabetic kidney were explored, in a temporal manner. The active subunit of NF-B, p65, was elevated in the diabetic animals in association with increased MCP-1 gene expression and macrophage infiltration. Second, the effects of treatment for 4 wk with the AII type 1 receptor antagonist valsartan, the AII type 2 receptor antagonist PD123319, or pyrrolidine dithiocarbamate, an inhibitor of NF-B and on these parameters were assessed. These treatments were associated with a reduction in p65 activation, MCP-1 gene expression, and macrophage infiltration. These findings demonstrate a role for activation of NF-B, in particular the p65 subunit, in the pathogenesis of early renal macrophage infiltration in experimental diabetes. In the context of the known proinflammatory effects of AII, it is postulated that the renoprotection conferred by angiotensin II receptor antagonism is at least partly related to the inhibition of NF-Bdependent pathways.

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

“…NF-B is composed of p50 and p65 subunits, among which p65 is a potent transcriptional activator, strongly promoting inflammatory reaction in kidney diseases (40). In this study, marked activation of p65, not p50, was closely correlated with the renal inflammation, consistent with the previous observation in experimental diabetic nephropathy (41). A putative NF-B regulatory site has been found in the mouse Smad7 promoter, suggesting a functional link between the NF-B and Smad7 (42).…”

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

“…Oxidative-nitrosative stress triggers several important downstream mechanisms, i.e., activation of mitogen-activated protein kinases [20,27], the nuclear transcription factor NF-κB [28,29], and upregulation of growth factors such as transforming growth factor-β (TGF-β) [14,15], cytokines [30,31], and vascular endothelial growth factor [32] implicated in diabetic renal disease [12,[27][28][29]33,34]. In vitro and in vivo studies in nondiabetic models of oxidative injury as well as animal and cell culture models of diabetic complications revealed that free radical and peroxynitrite-induced DNA single-strand breakage is also responsible for activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) and resultant energy failure, profound metabolic imbalances, and changes in transcriptional regulation and gene expression [35][36][37].…”

The Ubiquitin-Like Protein FAT10 Mediates NF-κB Activation

“…Aberrant regulation of NF-B may result in inflammatory and autoimmune diseases, impair antiviral immune responses, and contribute to malignant cellular transformation. 1-3 Activation of NF-B, with subsequent production of cytokines, chemokines, and adhesion molecules, is an important component of the pathogenesis of several forms of renal disease, including diabetic nephropathy (DN), 4,5 hypertensive nephrosclerosis (HN), 6,7 IgA nephropathy (IgAN), 8 membranous glomerulopathy, 9 and HIV-associated nephropathy. 10 -12 The canonical NF-B activation pathway can be induced by a variety of stimuli, including TNF-␣.…”