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.

Figure 1. Simplified model of ‘classic’ mesangial cell signaling abnormalities in early diabetic nephropathy

High extracellular glucose (and a number of other external signals) leads to increased mesangial cell glucose uptake via enhanced expression of the facilitative glucose transporter, GLUT1, which activates metabolic pathways that result in increased ROS and AGE generation. This in turn activates a number of signaling pathways that augment extracellular matrix production directly via PKC-β stimulation of AP-1 transcriptional activation, ERK pathways and, critically, TGF-β1 synthesis, which stimulates its signaling pathways in an autocrine and paracrine fashion to further enhance extracellular matrix protein synthesis. AGE: Advanced glycation end product; Ang II: Angiotensin II; DAG: Diacylglycerol; ERK: Extracellular signal-related kinase; PKC: Protein kinase C; ROS: Reactive oxygen species.

Figure 2. Enhanced mTOR signaling in diabetic glomerulopathy

Increased glucose uptake into diabetic mesangial cells (and perhaps other renal cells) leads to reduced AMPK activation and reduced association of TSC1 and TSC2, allowing for Rheb activation of mTOR. Increased glycolysis and activation of GAPDH can lead directly to Rheb activation of mTOR by reducing Rheb binding to GAPDH. AMPK: AMP kinase; S6K: S6 kinase; TSC: Tuberous sclerosis complex.