Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy

Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
Diabetes (Impact Factor: 8.1). 12/2008; 58(2):469-77. DOI: 10.2337/db08-1328
Source: PubMed


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.
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.
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.
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.

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    • "Transcriptome-based approach has been widely applied for studying diabetic nephropathy (DN) [3] [4], focal segmental glomerulosclerosis [5], chronic kidney disease progression [6], and glomerular disease classification [7]. The transcriptiomic approach is one of the most promising and advanced methods for identifying biomarkers and studying disease pathogenesis. "
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    • "We compared 40 SAGE-derived transcripts with the most divergent expression levels between ROP-Os/+ versus C57-Os/+ kidneys, with the human microarray expression data, comprised of samples obtained from micro-dissected human kidney biopsies from patients with FSGS [40]. The fold change and significance (assessed by q-value, corrected for multiple testing) was calculated by the Significance Analysis of Microarrays method (SAM) [41] using the MeV software from the Institute of Genome Research ( "
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