Abnormalities in signaling pathways in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is characterized by a plethora of signaling abnormalities that together ultimately result in the clinical and pathologic hallmarks of DN, namely progressive albuminuria followed by a gradual decline in glomerular filtration rate leading to kidney failure, and accompanied by podocyte loss, progressive glomerular sclerosis and, ultimately, progressive tubulointerstitial fibrosis. Over the past few years, the general understanding of the abnormalities in signaling pathways that lead to DN has expanded considerably. In this review, some of the important pathways that appear to be involved in driving this process are discussed, with special emphasis on newer findings and insights. Newer concepts regarding signaling changes in bradykinin, mTOR, JAK/STAT, MCP-1, VEGF, endothelial nitric oxide synthase, activated protein C and other pathways are discussed. Keywordsdiabetes; glomerulus; matrix proteins; signaling Diabetic nephropathy (DN) is usually manifested clinically by gradually worsening albuminuria, followed by a decline in glomerular filtration rate, which over years or decades leads to end-stage kidney disease in many patients with Type 1 or Type 2 diabetes. The pathologic correlates of this process are glomerular podocyte damage and loss [1], followed by the gradual, inexorable scarring of the renal glomerulus and then a similar fibrosing process

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

“…Pearson's test in the experimental groups revealed statistically significant correlations of renal NF-κB staining with the urine albumin-tocreatinine ratio (r=0.515, p=0. key pathogenic mechanisms and intracellular pathways leading to progression of diabetes complications are not modified by the current therapies [11,20]. Herein, we report that a cellpermeable peptide derived from the IKKα/βNBD domain inhibits the canonical NF-κB pathway and ameliorates renal dysfunction and atherosclerosis in diabetic mice primarily through the attenuation of local and systemic inflammation.…”

“…Clinical and experimental evidence implicates NF-κB activation and regulated genes in the early phases, progression and final complications of diabetes and, as such, its inhibition offers therapeutic intervention opportunities [11][12][13][14][15][16][17]. Although several NF-κB inhibitors have reached phase II/III clinical trials for inflammatory diseases [18,19], most research into cardiovascular or renal diseases is only in the preliminary experimental phase [20].…”

FOG2 Protein Down-regulation by Transforming Growth Factor-β1-induced MicroRNA-200b/c Leads to Akt Kinase Activation and Glomerular Mesangial Hypertrophy Related to Diabetic Nephropathy

“…It is characterized by glomerular mesangial expansion caused by mesangial cell hypertrophy, followed by extracellular matrix protein accumulation and subsequent glomerulosclerosis (1)(2)(3)(4). Cellular hypertrophy, a maladaptive increase in total cell volume and protein content without a concomitant increase in total cell number, is one of the early abnormalities found in DN (5).…”

Role of JAK3 in the Pathogenesis of Oxidative Stress-Induced Kidney Fibrosis

“…Liu et al (18) have demonstrated that STAT3 and JAK3 may act together, with JAK activation determining STAT activation, when investigating therapeutic effects of some cytokine inhibitors in diabetic nephropathy. There is other evidence that the JAK/STAT pathways act in diabetic nephropathy and may provide novel targets for new therapies (21)(22)(23). In this study, activated STAT3 (pSTAT3) expression was negligible in fibroblast and epithelial cell cultures treated with H 2 O 2 and so again little explanation was found for the discrepancies in JAK3 mRNA and protein after oxidative stress.…”