p38 MAPK inhibitors ameliorate target organ damage in hypertension: Part 2. Improved renal function as assessed by dynamic contrast-enhanced magnetic resonance imaging.
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 (> or =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 (approximately 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 (Kcl) 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.
Lenhard
Stephen C
SC
GlaxoSmithKline, Mail code UW2510, 709 Swedeland Rd., King of Prussia, PA 19406, USA.
Nerurkar
Sandhya S
SS
Schaeffer
Thomas R
TR
Mirabile
Rosanna C
RC
Boyce
Rogely W
RW
Adams
David F
DF
Jucker
Beat M
BM
Willette
Robert N
RN
D000419:Albuminuria / Q000652:urine; D000818:Animals; D003287:Contrast Media; D003404:Creatinine / Q000652:urine; D004041:Dietary Fats / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D019786:Gadolinium DTPA; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D007677:Kidney Function Tests; D008279:Magnetic Resonance Imaging; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000009:adverse effects; D020521:Stroke / Q000235:genetics / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases
D003287:Contrast Media; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D012982:Sodium, Dietary; D003404:Creatinine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; D019786:Gadolinium DTPA