Enhanced expression of janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy

Celine C. Berthier, Hongyu Zhang, Marylee Schin, Anna Henger, Robert G. Nelson, Berne Yee, Anissa Boucherot, Matthias A. Neusser, Clemens D. Cohen, Christin Carter-Su, Lawrence S. Argetsinger, Maria P. Rastaldi, Frank C. Brosius, Matthias Kretzler

Research output: Contribution to journalArticle

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 tubuloint- erstitium 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. RESEARCH DESIGN AND 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.

Original languageEnglish
Pages (from-to)469-477
Number of pages9
JournalDiabetes
Volume58
Issue number2
DOIs
Publication statusPublished - Feb 2009

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Berthier, C. C., Zhang, H., Schin, M., Henger, A., Nelson, R. G., Yee, B., Boucherot, A., Neusser, M. A., Cohen, C. D., Carter-Su, C., Argetsinger, L. S., Rastaldi, M. P., Brosius, F. C., & Kretzler, M. (2009). Enhanced expression of janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes, 58(2), 469-477. https://doi.org/10.2337/db08-1328