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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 2. Improved Renal Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Investigative and Cardiac Biology (S.C.L., S.S.N., B.M.J., R.N.W.), Laboratory Animal Sciences (T.R.S.), and Safety Assessment, Cardiovascular and Urogenital Center of Excellence in Drug Discovery (R.C.M., R.W.B., D.F.A.), GlaxoSmithKline, King of Prussia, Pennsylvania

Recent evidence suggests p38 mitogen-activated protein kinase (MAPK) signal transduction plays an important role in the pathogenesis of progressive renal disease. Using dynamic contrast enhanced magnetic resonance imaging (MRI), we evaluated chronic treatment with a p38 MAPK inhibitor, trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl-methoxypyridimidin-4-yl)imidazole (SB-239063), on renal function in a hypertension model of progressing renal dysfunction. Spontaneously hypertensive-stroke prone rats were placed on a high salt/fat diet (SFD) or maintained on normal chow diet (ND). SFD animals with albuminuria at 4 to 8 weeks (10 mg/day inclusion criteria), were randomized into p38 MAPK inhibitor treatment (SB-239063, 1200 ppm in diet) or vehicle groups. The progression of blood pressure and albuminuria during the treatment period (6 weeks) was decreased by 12 and 60%, respectively, in the SFD + SB-239063 versus SFD control group. Renal perfusion and filtration were assessed by in vivo MRI at the end of the study. Relative cortical perfusion was increased in the SFD + SB-239063 group compared with the SFD control group as reflected by a 29% decrease in time to peak of contrast agent in the cortex. Additionally, the regional renal glomerular filtration rate index (K_cl) was increased by 39% in the SFD + SB-239063 versus SFD control group and was normalized to the ND control group. Greater functional heterogeneity was observed in the SFD control versus SFD + SB-239063 or ND control group. All alterations of renal function were supported by histopathological findings. In conclusion, chronic treatment with a p38 MAPK inhibitor, SB-239063, attenuates functional and structural renal degeneration in a hypertensive model of established renal dysfunction.

Address correspondence to: Dr. Robert N. Willette, GlaxoSmithKline, Mail code UW2510, 709 Swedeland Rd., King of Prussia, PA 19406. E-mail: Robert_n_willette{at}gsk.com

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