Microinflammation in the pathogenesis of diabetic nephropathy

Abstract

Diabetic nephropathy is the leading cause of end-stage renal failure in developed countries. Furthermore, diabetic nephropathy is related to the risk of cardiovascular diseases and an increase in mortality of diabetic patients. Several factors are involved in the development of nephropathy, including glomerular hyperfiltration, oxidative stress, accumulation of advanced glycation end-products, activation of protein kinase C, acceleration of the polyol pathway and over-expression of transforming growth factor-β. Recently, accumulated data have emphasized the critical roles of chronic low-grade inflammation, 'microinflammation', in the pathogenesis of diabetic nephropathy, suggesting that microinflammation is a common mechanism in the development of diabetic vascular complications. Expression of cell adhesion molecules, chemokines and pro-inflammatory cytokines are increased in the renal tissues of diabetic patients and animals. Deficiency of pro-inflammatory molecules results in amelioration of renal injuries after induction of diabetes in mice. Plasma and urinary levels of cytokines, chemokines and cell adhesion molecules, are elevated and correlated with albuminuria. Several kinds of drugs that have anti-inflammatory actions as their pleiotropic effects showed renoprotective effects on diabetic animals. Modulation of the inflammatory process prevents renal insufficiency in diabetic animal models, suggesting that microinflammation is one of the promising therapeutic targets for diabetic nephropathy, as well as for cardiovascular diseases.

Keywords: Diabetic nephropathy; Inflammation; Microinflammation.

Figure 1

Mechanism of macrophage infiltration into the inflammatory lesion. Leukocyte infiltration is mediated by the adhesion molecules and chemokines. Selectin molecules mediate the leukocyte rolling on the vascular endothelial cells. Intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) promote firm attachment of leukocytes and endothelial cells. Monocyte chemoattractant protein‐1 (MCP‐1) induces the migration of leukocytes from vascular lumen into subendothelium.

Figure 2

Expression of intercellular adhesion molecule‐1 (ICAM‐1) in the (a) glomerulus and (b) interstitium. ICAM‐1 is expressed along endothelial cells in the glomerulus and interstitium. Macrophages are infiltrated in the (c) glomerulus and (d) interstitium.

Figure 3

Pathogenesis of diabetic nephropathy. AGEs, advanced glycation end‐products; PKC, protein kinase C; TGF‐β, transforming growth factor‐β.

Figure 4

Microinflammation and lifestyle‐related diseases. Microinflammation is a common mechanism of the development of lifestyle‐related diseases, including obesity‐related insulin resistance, diabetic vascular complications, cardiovascular diseases, chronic kidney disease (CKD), non‐alcoholic steatohepatitis (NASH) and some kinds of cancer. Albuminuria, C‐reactive protein (CRP) and plasma levels of cytokines might be surrogate clinical markers for the microinflammation.