title: Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy.
abstract: OBJECTIVE
  Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identify pathways that may be activated in humans but not in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure.
  
  
  METHODS
  Kidney biopsies were obtained from 74 patients (control subjects, early and progressive type 2 diabetic nephropathy). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed.
  
  
  RESULTS
  In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well as Stat-1 and -3 were expressed at higher levels in patients with diabetic nephropathy than in control subjects. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak-1, -2, and -3 and Stat-1 expression (R(2) = 0.30-0.44). Immunohistochemistry found strong Jak-2 staining in glomerular and tubulointerstitial compartments in diabetic nephropathy compared with control subjects. In contrast, there was little or no increase in expression of Jak/Stat genes in the db/db C57BLKS or diabetic DBA/2J mice.
  
  
  CONCLUSIONS
  These data suggest a direct relationship between tubulointerstitial Jak/Stat expression and progression of kidney failure in patients with type 2 diabetic nephropathy and distinguish progressive human diabetic nephropathy from nonprogressive murine diabetic nephropathy.
authors.affiliation: Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: MaryLee
authors.initials: M
authors.lastname: Schin
authors.forename: Anna
authors.initials: A
authors.lastname: Henger
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.forename: Berne
authors.initials: B
authors.lastname: Yee
authors.forename: Anissa
authors.initials: A
authors.lastname: Boucherot
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Neusser
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Christin
authors.initials: C
authors.lastname: Carter-Su
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Argetsinger
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3