Enhanced Expression of JAK-STAT Pathway Members in Human Diabetic Nephropathy

  1. Celine C. Berthier, PhD.1,
  2. Hongyu Zhang, M.D.1,
  3. MaryLee Schin, B.S.1,
  4. Anna Henger, PhD1,
  5. Robert G. Nelson, M.D., PhD2,
  6. Berne Yee, M.D.3,
  7. Anissa Boucherot, PhD.1,
  8. Matthias Neusser, M.D.4,
  9. Clemens Cohen, M.D.4,
  10. Christin Carter-Su, PhD.5,
  11. Lawrence S. Argetsinger, PhD.5,
  12. Maria Pia Rastaldi, M.D.6,
  13. Frank C. Brosius, M.D. (fbrosius{at}umich.edu)1,4 and
  14. Matthias Kretzler, M.D.1
  1. 1 Department of Internal Medicine – Nephrology, University of Michigan, Ann Arbor, Michigan, U.S.A
  2. 2 Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, U.S.A
  3. 3 Southwest Kidney Institute, Phoenix, Arizona, U.S.A
  4. 4 Department of Physiology, University of Zurich, Switzerland
  5. 5 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, U.S.A
  6. 6 Renal Research Laboratory, Fondazione D'Amico per la Ricerca sulle Malattie Renali and Fondazione IRCCS Policlinico, Milan, Italy

    Abstract

    Objective. Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy (DN) whereas tubulointerstitial injury and fibrosis are critical for progression of DN to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from DN patients to identify pathways that may be activated in humans but are not in murine models of DN that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis and kidney failure.

    Research Design and Methods. Kidney biopsies were obtained from 74 patients (controls, early and progressive type 2 DN). 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-DBA/2J mice, commonly studied murine models of DN, were analyzed.

    Results. In human glomeruli and tubulointerstitial samples, the Jak/Stat pathway was highly and significantly regulated. Jak-1, 2 and 3 as well as Stat-1 and Stat-3 were expressed at higher levels in patients with DN than in controls. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak1, 2, 3 and Stat1 expression (R2=0.30-0.44). Immunohistochemistry found strong Jak2 staining in glomerular and tubulointerstitial compartments in DN compared to controls. 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 DN and distinguishes progressive human DN from non-progressive murine DN.

    Footnotes

      • Received September 28, 2008.
      • Accepted November 12, 2008.

    This Article

    1. Published online before print November 18, 2008, doi: 10.2337/db08-1328
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