Mast Cell-Mediated Remodeling and Fibrinolytic Activity Protect against Fatal Glomerulonephritis

Abstract

Mast cells are detrimental in several inflammatory diseases; however, their physiological roles are also increasingly recognized. Recent data suggest that mast cells may also be involved in renal diseases. We therefore used congenitally mast cell-deficient W/Wv mice and normal +/+ littermates to assess their role in anti-glomerular basement membrane-induced glomerulonephritis. Following administration of anti-glomerular basement membrane Abs, W/Wv mice exhibited increased mortality as compared with +/+ mice owing to rapid deterioration of renal function. Reconstitution of the mast cell population in W/Wv mice restored protection. This was independent of activating FcγR, as protection was also obtained using mast cells deficient in FcRγ. Comparative histological analysis of kidneys showed that deterioration of renal function was caused by the presence of thick layers of subendothelial glomerular deposits in W/Wv mice, while +/+ mice or mast cell-reconstituted W/Wv mice showed significantly less. Deposits appeared during the early phase of disease and persisted thereafter, and were accompanied by enhanced macrophage recruitment. Immunohistochemical analysis revealed increased amounts of fibrin and type I collagen in W/Wv mice, which were also unable to maintain high tissue plasminogen activator and urinary-type plasminogen activator activity in urine in the heterologous phase of disease. Our results indicate that mast cells by their ability to mediate remodeling and repair functions are protective in immune complex-mediated glomerulonephritis.

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

“…Compelling evidence suggests that renal dysfunction in different forms of AKI is the outcome of secretion of immune mediators [5][6][7][8][9] and the activation of renal resident and recruited leukocytes 2,3,10,11 ; however, recent studies also suggested that certain cytokines 40 -43 and immune cells 23,44,45 may limit kidney injury by reducing the immune-mediated inflammatory response. 46 During renal injury, DCs are thought to contribute to renal inflammation and exacerbate kidney injury.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Most studies have suggested that a reduction of mast cells, or their typical enzyme chymase, increases fibrosis (52)(53)(54)(55)(56), whereas others suggest the opposite (57,58). Thus, the potential therapeutic value of mast cell manipulation in fibrosis is uncertain (23,59).…”

Role of Mast Cells in Progressive Renal Diseases

“…With the association of mast cells and T regulatory cells already established, 109 one study suggested that systemic mast cells infiltrate local lymphoid organs and activate regulatory T cells to confer protection. 123 Kanamaru et al 124 attributed the beneficial outcome of mast cellcompetent mice to improved repair function in the kidney. In a model of autoimmune immune complex disease, the absence of mast cells facilitated an altered pattern of disease but did not alter the severity of injury.…”