ABSTRACT
Progressive renal fibrosis is the final common pathway leading to renal failure irrespective of the initiating cause. Clinical studies of renal fibrosis found that prominent mast cell accumulation correlated with worse outcomes. Mast cells are pluripotent innate immune cells that synthesize and secrete profibrotic mediators. Here we use mast cell-deficient (Kit(W-sh/W-sh)) mice to define a functional pathogenic role for these cells in the development of renal fibrosis. Intrarenal collagen deposition was significantly decreased in mast cell-deficient compared to wild-type mice 7 and 14 days after unilateral ureteric obstruction. The intrarenal expression of mRNAs for transforming growth factor-ß, α-smooth muscle actin, chemokines, and renal macrophages and CD4(+) T cells were also decreased in mast cell-deficient mice. Reconstitution of the mast cell population in mast cell-deficient mice with wild-type bone marrow-derived mast cells restored the pattern and intensity of renal fibrosis to levels seen in wild-type mice following ureteric ligation. Interestingly, the mast cells were recruited, activated, and degranulated within 6 h of ureteric ligation. A mast cell stabilizer that impairs degranulation, disodium chromoglycate, significantly attenuated renal fibrosis following ureteric ligation in wild-type mice. Thus, mast cells promote renal fibrosis and their targeting may offer therapeutic potential in the treatment of renal fibrosis.
Subject(s)
Cell Degranulation , Kidney Diseases/etiology , Kidney/immunology , Mast Cells/immunology , Ureteral Obstruction/complications , Actins/genetics , Actins/metabolism , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Degranulation/drug effects , Cells, Cultured , Chemokines/genetics , Chemokines/metabolism , Collagen/metabolism , Cromolyn Sodium/pharmacology , Disease Models, Animal , Disease Progression , Fibrosis , Gene Expression Regulation , Hydronephrosis/etiology , Hydronephrosis/immunology , Hydronephrosis/pathology , Kidney/drug effects , Kidney/pathology , Kidney Diseases/genetics , Kidney Diseases/immunology , Kidney Diseases/pathology , Kidney Diseases/prevention & control , Macrophages/immunology , Male , Mast Cells/drug effects , Mast Cells/transplantation , Matrix Metalloproteinase 12/genetics , Matrix Metalloproteinase 12/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Phenotype , Proto-Oncogene Proteins c-kit/genetics , Time Factors , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Ureteral Obstruction/genetics , Ureteral Obstruction/immunology , Ureteral Obstruction/pathologyABSTRACT
Leukocyte recruitment contributes to acute kidney injury (AKI), but the mechanisms by which leukocytes promote injury are not completely understood. The degranulation of mast cells releases inflammatory molecules, including TNF, but whether these cells participate in the pathogenesis of AKI is unknown. Here, we induced AKI with cisplatin in mast cell-deficient and wild-type mice. Compared with wild-type mice, deficiency of mast cells attenuated renal injury, reduced serum levels of TNF, and reduced recruitment of leukocytes to the inflamed kidney. Mast cell-deficient mice also exhibited significantly lower intrarenal expression of leukocyte chemoattractants. Mast cell-deficient mice reconstituted with mast cells from wild-type mice exhibited similar cisplastin-induced renal damage and serum levels of TNF as wild-type mice. In contrast, mast cell-deficient mice reconstituted with mast cells from TNF-deficient mice continued to demonstrate significant attenuation of cisplatin-induced renal injury. Furthermore, the mast-cell stabilizer sodium chromoglycate also significantly abrogated renal injury in this model of AKI. Taken together, these results suggest that mast cells mediate AKI through the production of TNF.
