Inhibition of p38 mitogen-activated protein kinase augments progression of remnant kidney model by activating the ERK pathway.
p38, a mitogen-activated protein kinase, is a major intracellular signaling molecule involved in inflammation. To test the hypothesis that p38 mediates renal disease progression, we administered a novel p38 alpha inhibitor, NPC31169, to rats with remnant kidneys (RKs). RK rats showed increased p38 activation at 9 weeks (by p38 kinase assay), which was blocked by the inhibitor. In contrast to our expectation, treatment with the NPC31169 resulted in worse renal function, more proteinuria, and more severe glomerulosclerosis and tubulointerstitial injury. p38 inhibition resulted in marked cell proliferation in RK rats, with more proliferating tubular cells, myofibroblasts, and macrophages. In contrast, p38 suppression resulted in less tubular cell apoptosis. Interestingly, Western blot demonstrated increased ERK1/2 phosphorylation in p38-treated rats. No histological changes were observed in p38 inhibited sham-operated rats. Our findings indicate that, whereas blocking p38 usually shows benefit in inflammatory disease, in this model p38 inhibition resulted in accelerated renal progression. We conclude that blocking p38-dependent inflammation may have resulted in enhanced proliferation and increased ERK1/2 activation, and thereby explains the worse renal lesions observed.
Ohashi
Ryuji
R
Division of Nephrology, Baylor College of Medicine, Houston Texas 77030, USA. rohasi@bcm.tmc.edu
Nakagawa
Takahiko
T
Watanabe
Susumu
S
Kanellis
John
J
Almirez
Ramona G
RG
Schreiner
George F
GF
Johnson
Richard J
RJ
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases