title: Predictive significance of kidney myeloid-related protein 8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases.
abstract: 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.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takashige
authors.initials: T
authors.lastname: Kuwabara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan ; Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan ; Department of EBM Research, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasahara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imamaki
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koga
authors.affiliation: Department of Nephrology, Osaka Red Cross Hospital, Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
authors.affiliation: Department of EBM Research, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.affiliation: Department of EBM Research, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.affiliation: Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Konishi
authors.affiliation: Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Imanishi
authors.affiliation: Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan ; Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
mesh_terms: D000328:Adult; D000818:Animals; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism* / Q000652:urine; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D011379:Prognosis
chemical_list: D040501:Calgranulin A