||Celine C. Berthier, PhD., Hongyu Zhang, M.D., MaryLee Schin, B.S., Anna Henger,
PhD, Robert G. Nelson, M.D., PhD, Berne Yee, M.D., Anissa Boucherot, PhD.,
Christin Carter-Su, PhD., Lawrence S. Argetsinger, PhD., Maria Pia Rastaldi,
M.D., Frank C. Brosius, M.D., Matthias Kretzler, M.D
||Frank Brosius on 3/28/2008
|Volume : Pages
||Epub : 469 - 477
||Objective. Glomerular mesangial expansion and podocyte loss are important early
features of diabetic nephropathy (DN) whereas tubulointerstitial injury and
fibrosis are critical for the progression of DN to kidney failure. Therefore, we
analyzed the expression of genes in both glomeruli and tubulointerstitium in
kidney biopsies from DN patients to identify pathways that may be activated in
both regions, but that are not activated 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 DN). Glomerular and tubulointerstitial mRNAs
were microarrayed, followed by bioinformatic and pathway analyses. Gene
expression changes were confirmed by real-time RT-PCR and immunohistological
staining. Samples from db/db C57BLKS mice, a commonly studied murine model of
DN, were similarly 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
serum creatinine strongly correlated with tubulointerstitial Jak1, 2, 3, Stat1
and Stat3 expression (R2=0.36-0.75). Immunohistochemistry found strong Jak2
staining in glomerular and tubulointerstitial compartments in DN compared to
controls. In contrast, there was no or little increase in expression of any of
the Jak/Stat genes in the db/db C57.BKS mice.
Conclusions. These data suggest a direct relationship between tubulointerstitial
Jak/Stat expression and progression of kidney failure in patients with DN and
distinguishes progressive human DN from non-progressive murine DN.