Inflammatory cytokines as predictive markers for early detection and progression of diabetic nephropathy

Abstract

Diabetic nephropathy is a major complication of diabetes mellitus and the leading cause of end-stage renal disease. Both hyperglycemia and hypertension (systemic and/or intraglomerular) are established causal factors for diabetic nephropathy. Nonetheless, there is growing evidence that activated innate immunity and inflammation are also contributing factors to the pathogenesis of diabetic nephropathy. This notion is based on increasing evidence indicating that both cytokines-chemokines and pro-fibrotic growth factors are important players in the progression of diabetic nephropathy, effectively accelerating and exacerbating inflammatory and fibrotic processes leading to end-stage renal disease. In this review, we focus on several predominant cytokines-chemokines as potential predictive markers for diabetic nephropathy. These cytokines-chemokines may also be helpful as biomarkers to monitor the progression of the disease and the impact of interventional modalities aimed at halting eventual manifestation of end-stage renal disease in diabetic patients.

Fig. 1

A number of risk factors contribute to eventual manifestation of insulin resistance/hyperglycemia. In turn, hyperglycemia results in a myriad of metabolic and hemodynamic abnormalities that are intimately associated with microvascular complication of diabetes including nephropathy

Fig. 2

Schematic diagram showing the proposed relationship between hyperglycemia, oxidative stress and inflammatory cytokines production in the pathogenesis and progression of diabetic nephropathy. ROS: reactive oxygen species; TNF-α: tumor necrosis factor-α; NFκB: nuclear transcription factor-κ; MCP-1: monocyte chemoattractant protein-1; CAMs: cellular adhesion molecules; NO: nitric oxide; TGF-β: transforming growth factor-β; CTGF: connective tissue growth factor; CRP: C-reactive protein

Fig. 3

shows immuno-histochemical assessment of collagen IV deposition in the kidney section from streptozotocin-induced type 1 diabetic rats and sham control rat. Collagen IV deposition (dark brown) increased in the kidney section from diabetic vs. sham control rat. Images are shown at 200×

Fig. 4

Bar graphs show fasting plasma glucose and insulin levels as well as the homeostatic model assessment (HOMA) insulin resistance index of (6-month-old) OZR, expressed as percent of values of LZR. Also shown are hematoxylin-eosin stained sections of pancreas from LZR and OZR rats (insets, 100×)

Fig. 5

Oil-Red-O stained kidney tissue from (6-month-old) OZR show more numerous lipid droplets compared to age-matched LZR (panels a and b; 400×). Also shown are immunostaining for CD 68 positive cells (arrows) in kidney tissue from experimental groups (panels c and d; 200×)

Fig. 6

Bar graphs show urinary excretions of albumin and monocyte chemoattractant protein-1 (MCP-1) expressed as the percent of the LZR group (panel A). Panel B shows that renal tissue from (6-month-old) OZR displayed higher level of intercellular adhesion molecule-1 (ICAM-1) compared to age-matched LZR. Also shown are representative blots for ICAM-1 and β-actin (i.e., loading control). Data are means ± SEM of 7–9 animals/group. *p < 0.05 compared to LZR