Inflammation in diabetic nephropathy

Abstract

Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies.

Figure 1

The inflammatory amplification loop in the diabetic kidney. Circulating immune cells such as monocytes are recruited into the diabetic kidney due to upregulation of adhesion molecules such as ICAM-1. Chemokines such as MCP-1 act as chemoattractants which promote accumulation of the immune cells in the kidney. These immune cells are activated by numerous signals such as the ligation of c-fms by CSF-1, receptor for AGE by AGEs, and the Fcγ receptors by antioxidized LDL immune complexes. CSF-1 also promotes the maturation, proliferation, and survival of monocyte-macrophages. Activated immune cells act as inflammatory cells and elaborate proinflammatory cytokines and reactive oxygen species (ROS), which trigger a cell signalling cascade mediated by the stress-activated protein kinases, p38 MAPK, and JNK. These kidney cells then respond by the production of chemokines such as MCP-1 and CSF-1, and profibrotic factors such as TGF-β which increase extracellular matrix production by mesangial cells and interstitial fibroblasts. Ultimately, there is cellular injury and progressive fibrosis within the diabetic kidney.