Abstract
Activation of p38 mitogen-activated protein kinase (MAPK) is associated with tissue fibrosis, and inhibition of p38 MAPK can attenuate the progression of fibrosis. We aimed to investigate whether p38 MAPK activity in kidney tissue confirmed by immunohistochemical staining is associated with renal tubulointerstitial fibrosis in chronic kidney disease patients with IgA nephropathy. We collected kidney biopsy specimens from 341 IgA nephropathy patients and 15 control patients to identify the clinical and histopathological factors associated with kidney tubulointerstitial fibrosis and to find an association between kidney phosphorylated p38 immunoactivity and pathological grading. In addition, we aimed to investigate whether the anti-fibrotic effect of p38 MAPK inhibition can be identified by assessing the immunostaining intensity of phosphorylated p38 in kidney tissue. A renal tubulointerstitial fibrosis model was introduced using 7-week-old C57BL/6 mice subjected to unilateral ureteral obstruction (UUO). The p38 MAPK inhibitor SB-731445 was injected intraperitoneally every day for 7 days, and changes in renal fibrosis-associated markers were investigated. Assessment of kidney biopsy specimens from IgA nephropathy patients revealed that the degree of interstitial fibrosis was significantly associated with the tissue immunoactivity of phosphorylated p38. High-grade interstitial fibrosis was associated with a low glomerular filtration rate, high proteinuria, and high-grade histopathological changes, including tubular atrophy, interstitial inflammation, and glomerular sclerosis. In a mouse UUO model, renal protein expression of COL1 and phosphorylated p38 were significantly increased, and the protein expression of COL1 and phosphorylated p38 decreased in mice administered 10 mg/kg/day p38 MAPK inhibitor. We found that kidney interstitial fibrosis is associated with increased immunoactivity of phosphorylated p38 in a UUO mouse model and in human IgA nephropathy patients and that the anti-fibrotic effect of p38 MAPK inhibition can be confirmed using immunohistochemical staining for phosphorylated p38 in kidney tissue.