Inhibition of p38 mitogen-activated protein kinase and transforming growth factor-beta1/Smad signaling pathways modulates the development of fibrosis in adriamycin-induced nephropathy.
Inflammation and fibrogenesis are the two determinants of the progression of renal fibrosis, the common pathway leading to end-stage renal disease. The p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta1/Smad signaling pathways play critical roles in inflammation and fibrogenesis, respectively. The present study examined the beneficial renoprotective effect of combination therapy using the p38 MAPK pathway inhibitor (SB203580) and a TGF-beta receptor I (ALK5) inhibitor (ALK5I) in a mouse model of adriamycin (ADR) nephrosis. The p38 MAPK and TGF-beta1/Smad2 signaling pathways were activated in ADR-induced nephropathy in a sequential time course manner. Two weeks after ADR injection, the combined administration of SB203580 (1 mg/kg/24 hours) and ALK5I (1 mg/kg/24 hours) markedly reduced p38 MAPK and Smad2 activities. Moreover, the co-administration of SB203580 and ALK5I to ADR-injected mice resulted in a down-regulation of total and active TGF-beta1 production, reduced myofibroblast accumulation, and decreased expression of collagen type IV and fibronectin. In these mice, retardation in the development of glomerulosclerosis and interstitial fibrosis was observed. In conclusion, although p38 MAPK and TGF-beta1/Smad signaling pathways are distinct they coordinate the progression of renal fibrosis in ADR nephrosis. The co-administration of a p38 MAPK inhibitor and an ALK5 inhibitor may have potential applications in the treatment of renal fibrosis.
Li
Jinhua
J
Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria 3800, Australia.
Campanale
Naomi Vittoria
NV
Liang
Rong Jiao
RJ
Deane
James Antony
JA
Bertram
John Frederick
JF
Ricardo
Sharon Denise
SD
D000199:Actins / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors; D000818:Animals; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032342:Muscle Cells / Q000187:drug effects; D009401:Nephrosis / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000199:Actins; D007093:Imidazoles; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; C093642:SB 203580