Inhibition of Jak/STAT signaling ameliorates mice experimental nephrotic syndrome. 2007

Rong Li, and Niansheng Yang, and Lili Zhang, and Yuefang Huang, and Rui Zhang, and Fang Wang, and Mingqian Luo, and Yingjie Liang, and Xueqing Yu
Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.

OBJECTIVE This study investigated the role of JAK/STAT, an important pathway for cytokine signal transduction, in the progression of chronic glomerular diseases. METHODS BALB/c mice received a single intravenous injection of adriamycin (10 mg/kg) were sacrificed 2, 4 and 6 weeks later. In the second study, treatment with the selective JAK2 inhibitor AG490 (15 mg/kg, q.d., i.p.) or vehicle was started 5 days after adriamycin injection. Functional and pathologic markers, inflammatory infiltration, expression of pro-inflammatory cytokines and phosphorylation of JAK2/STATs were assessed. RESULTS JAK/STAT signaling was activated in adriamycin nephropathy. Phosphorylation of JAK2, STAT1 and STAT3 was significantly inhibited by AG490 (p <0.01). Compared to the vehicle-treated controls, AG490 treatment did not reduce proteinuria 2 weeks after induction of the disease, but resulted in significant decrease in proteinuria and serum creatinine at week 6 (p <0.05). Glomerulosclerosis, tubulointerstitial lesions and renal alpha-SMA expression were also significantly suppressed by AG490 treatment at week 6 (p < 0.01). In addition, AG490 inhibited the expression of MCP-1 mRNA, accompanied by reduced interstitial infiltration of macrophages and T cells (p <0.05). CONCLUSIONS This study suggests that activation of JAK/STAT signaling is involved in the progression of glomerular diseases with proteinuric state.

UI MeSH Term Description Entries
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D008297 Male Males
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D009404 Nephrotic Syndrome A condition characterized by severe PROTEINURIA, greater than 3.5 g/day in an average adult. The substantial loss of protein in the urine results in complications such as HYPOPROTEINEMIA; generalized EDEMA; HYPERTENSION; and HYPERLIPIDEMIAS. Diseases associated with nephrotic syndrome generally cause chronic kidney dysfunction. Childhood Idiopathic Nephrotic Syndrome,Frequently Relapsing Nephrotic Syndrome,Multi-Drug Resistant Nephrotic Syndrome,Pediatric Idiopathic Nephrotic Syndrome,Steroid-Dependent Nephrotic Syndrome,Steroid-Resistant Nephrotic Syndrome,Steroid-Sensitive Nephrotic Syndrome,Multi Drug Resistant Nephrotic Syndrome,Nephrotic Syndrome, Steroid-Dependent,Nephrotic Syndrome, Steroid-Resistant,Nephrotic Syndrome, Steroid-Sensitive,Nephrotic Syndromes,Steroid Dependent Nephrotic Syndrome,Steroid Resistant Nephrotic Syndrome,Steroid Sensitive Nephrotic Syndrome,Steroid-Dependent Nephrotic Syndromes,Steroid-Resistant Nephrotic Syndromes,Steroid-Sensitive Nephrotic Syndromes,Syndrome, Nephrotic,Syndrome, Steroid-Sensitive Nephrotic
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D050791 STAT Transcription Factors A family of transcription factors containing SH2 DOMAINS that are involved in CYTOKINE-mediated SIGNAL TRANSDUCTION. STAT transcription factors are recruited to the cytoplasmic region of CELL SURFACE RECEPTORS and are activated via PHOSPHORYLATION. Once activated they dimerize and translocate into the CELL NUCLEUS where they influence GENE expression. They play a role in regulating CELL GROWTH PROCESSES and CELL DIFFERENTIATION. STAT transcription factors are inhibited by SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS and PROTEIN INHIBITORS OF ACTIVATED STAT. STAT (Signal Transducers and Activators of Transcription) Proteins,Transcription Factors, STAT

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