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

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 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 ( 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.

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

“…As glomerulosclerosis become severe, glomerular filtration rate (GFR) declines, and DN progresses to end-stage renal disease. Numerous molecular pathways have been identified that link the metabolic abnormalities of diabetes to glomerular hyperfiltration and glomerular cell activation including hyperglycaemia and the generation of glycation end products [21], JAK/STAT expression [4], p38 MAPK [1], local TGF-β production [12,23], endothelial dysfunction [25], oxidative stress [6] and activation of NF-κB-dependent inflammatory genes [27].…”

The Role of STAT3 Activation in Glomerulonephritis

“…In addition, mesangial expansion and podocyte loss in the glomeruli are important early features of diabetic nephropathy. JAK1, JAK2, and JAK3 as well as STAT1 and STAT3 are expressed at higher levels in patients with diabetic nephropathy than in control subjects (Berthier et al, 2009). Immunohistochemistry showed strong JAK2 staining in glomerular and tubulointerstitial compartments of patients with diabetic nephropathy compared with control subjects.…”

Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology

“…In two studies, analysis of kidney tissue mRNA expression in human diabetic kidney biopsies compared with normal human samples and diabetic mouse models revealed an association of the JAK-STAT pathway expression with human disease progression (32,33). Baricitinib is a small molecule inhibitor of JAK-1 and -2, and it was previously approved for the treatment of rheumatoid arthritis.…”