Role of the JAK/STAT signaling pathway in diabetic nephropathy

Abstract

Excessive cellular growth is a major contributor to pathological changes associated with diabetic nephropathy. In particular, high glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. Glomerular mesangial cells respond to traditional growth factors, although in diabetes this occurs in the context of an environment enriched in both circulating vasoactive mediators and high glucose. For example, the vasoactive peptide ANG II has been implicated in the pathogenesis of diabetic renal disease, and recent findings suggest that high glucose and ANG II activate intracellular signaling processes, including the polyol pathway and generation of reactive oxygen species. These pathways activate the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascades in glomerular mesangial cells. Activation of the JAK/STAT signaling cascade can stimulate excessive proliferation and growth of glomerular mesangial cells, contributing to diabetic nephropathy. This review focuses on some of the key elements in the diabetic microenvironment, especially high glucose and the accumulation of advanced glycoxidation end products and considers their impact on ANG II and other vasoactive peptidemediated signaling events in vitro and in vivo. ANG II; high glucose; glomerular mesangial cells; advanced glycoxidation end products GLOMERULAR MESANGIAL CELLS possess both contractile and mitogenic properties and contribute to the physiological regulation of glomerular dynamics (30,73). Growth factors have a maladaptive role in the glomerular damage accompanying experimental and human glomerulonephritis. This is especially evident in diabetic nephropathy through enlargement of the glomerular remnant and mesangial matrix expansion associated with the accumulation of extracellular matrix proteins synthesized by glomerular mesangial cells (12,30,73). The vasoactive peptide ANG II, not usually considered in the context of traditional growth factors, has been implicated in both normal and diabetic cellular growth (3, 64). Our group has found that activation of the Janus kinase (JAK)/signal transducers and activation of transcription (STAT) pathway is essential for ANG II-induced growth of glomerular mesangial cells (4,70). In addition, we have recently shown that high glucose augments ANG II-induced activation of the JAK/STAT pathway in rat kidney glomeruli (7) and that this pathway contributes importantly to production of the cytokine TGF-␤ as well as the extracellular matrix proteins collagen IV and fibronectin (70). Furthermore, recent studies also demonstrate that high glucose induces intracellular production of reactive oxygen species (ROS) (24), which have been shown to augment ANG II-induced signaling cascades and to activate JAK and STAT proteins (63,68).Renal disease is one of the leading causes of morbidity and mortality in patients with diabetes mellitus, and ANG II has been implicated in the pathogenesis of maladaptive growth in renal tissues...

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

“…Owing to its chaperoning function, HSP90 regulates the stability and the activation of NF-kB and STAT signaling pathways by direct association and stabilization of their respective activating kinases, IKK (42) and JAK2 (43). Accordingly, the efficacy of HSP90 inhibitors in animal models has been linked to the disruption of the IKK complex and JAK2 protein stability, further inhibiting downstream transcription factors such as p50/p65 NF-kB (44) and STAT1/STAT3/STAT5 (45). Dysregulated NF-kB and STAT pathways contribute to diabetic nephropathy and atherosclerosis by inducing the transcription of many genes associated with inflammation, renal fibrosis (45)(46)(47), and the proatherogenic state (23,48).…”

“…Accordingly, the efficacy of HSP90 inhibitors in animal models has been linked to the disruption of the IKK complex and JAK2 protein stability, further inhibiting downstream transcription factors such as p50/p65 NF-kB (44) and STAT1/STAT3/STAT5 (45). Dysregulated NF-kB and STAT pathways contribute to diabetic nephropathy and atherosclerosis by inducing the transcription of many genes associated with inflammation, renal fibrosis (45)(46)(47), and the proatherogenic state (23,48). We have previously tested a number of potential novel approaches (e.g., kinase inhibitors, permeable peptides, and gene therapy) to tackle diabetic nephropathy and atherosclerosis by separately inhibiting the STAT and NF-kB pathways (23,26,28,29).…”

Reduction of Stat3 Activity Attenuates HIV-Induced Kidney Injury

“…The JAK-Stat3 pathway plays an important role in the pathogenesis of diabetic nephropathy. 34,35 Selective pharmacologic inhibition of JAK2 (AG490) ameliorates nephrotic syndrome in adriamycin-induced nephropathy. 36 Stat3 is also a key mediator in Gas6 nephropathy.…”

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

“…In contrast to the microarray data, real-time RT-PCR found that mRNA expression of most Jak/Stat family members remained elevated in glomeruli from progressive diabetic nephropathy patients compared with control samples (Supplementary Table 5A). In the remainder of our study, we focused on Jak-2 since it appears to play a key role in proinflammatory responses in both glomerular and tubular cells (24). Jak-2 mRNA levels were significantly increased in the glomeruli of early diabetic nephropathy patients and in the tubulointerstitium of patients with progressive diabetic nephropathy compared with those of control subjects ( Fig.…”