Upregulated IL-18 expression in type 2 diabetic subjects with nephropathy: TGF-beta1 enhanced IL-18 expression in human renal proximal tubular epithelial cells

Diabetes Res Clin Pract. 2009 Feb;83(2):190-9. doi: 10.1016/j.diabres.2008.11.018. Epub 2008 Dec 24.


Aim: In order to clarify the importance of Interleukin (IL)-18 in the development of diabetic nephropathy (DN), we evaluated the expressions of IL-18 in diabetic kidney.

Methods: We performed immmunohistochemical analysis of IL-18 and IL-18 receptor (IL-18 R) in human kidney tissue derived from 12 subjects with type 2 diabetes and overt nephropathy, and compared with those in 7 subjects with minimal change nephrotic syndrome (MCNS). In addition, we examined the regulation of IL-18 expression using human renal proximal tubular epithelial cells (HRPTECs) in culture.

Results: IL-18 expression in tubular cells was observed in higher rate (83%) in patients with diabetes, whereas one positive specimen (14.3%) for IL-18 in patients with MCNS. In contrast, IL-18 R was expressed in glomerular mesangial cells and endothelial cells as well as tubular cells, similarly in almost of both groups. Exposure to transforming growth factor beta (TGF-beta(1)) led to two-fold increase in IL-18 gene expression in HRPTECs, and mitogen-activated protein kinases (MAPK) inhibitors abolished TGF-beta(1)-induced IL-18 mRNA expression. Western blot analysis showed the IL-18 protein in HRPTECs.

Conclusion: The present data indicate that IL-18 is overexpressed in human tubular epithelial cells in diabetic nephropathy, probably through the activation of MAPK pathways induced by TGF-beta(1).

MeSH terms

  • Aged
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Female
  • Humans
  • Interleukin-18 / genetics*
  • Interleukin-18 / metabolism
  • Interleukin-18 Receptor alpha Subunit / genetics
  • Interleukin-18 Receptor alpha Subunit / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Male
  • Middle Aged
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta1 / pharmacology*
  • Up-Regulation / drug effects


  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Transforming Growth Factor beta1
  • Extracellular Signal-Regulated MAP Kinases
  • Caspase 1