Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy
Copyright policy )Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy
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. 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 (R2 = 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.
- Southwest Kidney Institute United States
- National Institute of Health Pakistan
- University of Michigan–Ann Arbor United States
- National Institutes of Health United States
- University of Zurich Switzerland
Adult, Male, Complications, Blotting, Western, Gene Expression, 610 Medicine & health, 10052 Institute of Physiology, Mice, Animals, Humans, 10035 Clinic for Nephrology, Diabetic Nephropathies, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Janus Kinase 3, Janus Kinase 1, Janus Kinase 2, Middle Aged, Immunohistochemistry, Mice, Inbred C57BL, 2712 Endocrinology, Diabetes and Metabolism, STAT1 Transcription Factor, 2724 Internal Medicine, Mice, Inbred DBA, 570 Life sciences; biology, Female, 10029 Clinic and Policlinic for Internal Medicine, Reactive Oxygen Species
Adult, Male, Complications, Blotting, Western, Gene Expression, 610 Medicine & health, 10052 Institute of Physiology, Mice, Animals, Humans, 10035 Clinic for Nephrology, Diabetic Nephropathies, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Janus Kinase 3, Janus Kinase 1, Janus Kinase 2, Middle Aged, Immunohistochemistry, Mice, Inbred C57BL, 2712 Endocrinology, Diabetes and Metabolism, STAT1 Transcription Factor, 2724 Internal Medicine, Mice, Inbred DBA, 570 Life sciences; biology, Female, 10029 Clinic and Policlinic for Internal Medicine, Reactive Oxygen Species
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).288 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!