p38 MAPK activity is associated with the histological degree of interstitial fibrosis in IgA nephropathy patients

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.

High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice

“…Further, p38MAPK + immune-reactivity is shown to induce renal interstitial fibrosis in mice leading to proteinuria and renal tissue inflammation [49], similar to the observations determined herein. Interestingly, pharmacological inhibitors of p38 MAPK (SB-731445, FR167653) effectively reduce its phosphorylation and ability to induce fibrosis in renal tissues [49,54], implicating this pathway in renal tissue fibrosis. In our experiments, this was evidenced by marked increases in p38MAPK phosphorylation in renal epithelial and interstitial cells from mice treated with SAA and assigned to the old cohort, which aligns with the time where enhanced fibrosis is anticipated.…”

“…Activation of p38MAPK induces fibrosis in cardiac [50], pulmonary [51,52], and peritoneal membranes [53]. Further, p38MAPK + immune-reactivity is shown to induce renal interstitial fibrosis in mice leading to proteinuria and renal tissue inflammation [49], similar to the observations determined herein. Interestingly, pharmacological inhibitors of p38 MAPK (SB-731445, FR167653) effectively reduce its phosphorylation and ability to induce fibrosis in renal tissues [49,54], implicating this pathway in renal tissue fibrosis.…”

“…Consistent with this notion, P38 mitogen-activated protein kinase (p38MAPK + ) immunofluorescence was increased in SAA-treated mice compared to vehicle and LPS controls while pretreatment with HDL attenuated both oxidative damage (3Cl-Tyr) and p38MAPK + immunoreactivity in renal tissues. P38MAPK is central to an intracellular signal transduction pathway involved in the activation of profibrotic and pro-inflammatory mediators [49]. Activation of p38MAPK induces fibrosis in cardiac [50], pulmonary [51,52], and peritoneal membranes [53].…”

Coagulation parameters are associated with the prognosis of immunoglobulin A nephropathy: a retrospective study

“…Considering that T score is a well-recognized independent predictor of IgAN, it is worth exploring the possible risk factors associated with T. Studies have reported that tubulointerstitial injury of IgAN was associated with trefoil factor 3 mRNA [15], p38 MAPK activity [16], BMI [17], serum matrix metalloproteinase-7 level [18]. In this study, we demonstrated the signi cance of coagulation parameters PT and APTT in the tubulointerstitial injury of IgAN.…”

Myelodysplastic syndrome: the other cause of anemia in end-stage renal disease patients undergoing dialysis

“…It is activated and phosphorylated in hematopoietic progenitor cells in MDS patients and is probably related to myelosuppressive cytokines (IFN-α, IFN-β, IFN-γ, TGF-β, and TNF-α) 32 . Interestingly, p38 MAPK activity is also associated with interstitial fibrosis in IgA nephropathy patients 35 and in diabetic nephropathy 36 . The inhibition of activated p38 MAPK can improve renal function in type 2 diabetic rats 36 .…”