Predictive significance of kidney myeloid-related protein 8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases

PLoS One. 2014 Feb 18;9(2):e88942. doi: 10.1371/journal.pone.0088942. eCollection 2014.


Background and objective: We have reported that toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), play an important role in the progression of diabetic nephropathy in mice. The aim of this study was to evaluate significance of kidney MRP8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases.

Methods: In diabetic, obese or control subjects, MRP8 mRNA and protein expression levels in renal biopsy samples were determined by real-time RT-PCR and immunohistochemistry (n = 28 and 65, respectively), and their associations with baseline and prognostic parameters were analyzed. Effects of MRP8 upon pro-inflammatory gene expressions were examined using macrophages.

Results: Kidney MRP8 gene and protein expression levels were elevated in obese or diabetic groups compared to control group. Among all subjects, by univariate linear regression analysis, glomerular MRP8-positive cell count and tubulointerstitial MRP8-positive area at baseline were both, respectively, correlated not only with various known risk factors for diabetic nephropathy (such as systolic blood pressure, proteinuria and serum creatinine) but also with extent of glomerulosclerosis and tubulointerstitial fibrosis. Independent factors predicting urinary protein levels a year later were examined by multivariate analysis, and they included glomerular MRP8-positive cell count (β = 0.59, P<0.001), proteinuria (β = 0.37, P = 0.002) and systolic blood pressure (β = 0.21, P = 0.04) at baseline, after adjustment for known risk factors. MRP8 protein expression was observed in CD68-positive macrophages and atrophic tubules. In cultured mouse macrophages, MRP8 protein induced proinflammatory cytokine expressions and also triggered auto-induction of MRP8 in a TLR4-dependent manner.

Conclusions: Glomerular MRP8 expression appears to be associated with progression of proteinuria in obese or type 2 diabetic patients, possibly by inducing inflammatory changes in macrophages through TLR4 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Calgranulin A / genetics
  • Calgranulin A / metabolism*
  • Diabetes Mellitus, Type 2 / complications*
  • Female
  • Gene Expression Regulation*
  • Humans
  • Kidney / metabolism*
  • Kidney Diseases / complications*
  • Kidney Diseases / diagnosis
  • Kidney Diseases / metabolism*
  • Kidney Diseases / urine
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Obesity / complications*
  • Prognosis


  • Calgranulin A

Grant support

This work was supported in part by Grant-in-Aid for Diabetic Nephropathy and Nephrosclerosis Research from the Ministry of Health, Labour and Welfare of Japan (to KM), research grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (to TK, KM, and MM), from the Japan Foundation for Applied Enzymology (to TK) and from the Smoking Research Foundation (to MM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.