Involvement of macrophage migration inhibitory factor (MIF) in experimental uric acid nephropathy

Background: Deposition of uric acid in the kidney can lead to progressive t ubulointerstitial injury with granuloma formation. We hypothesized that uri c acid crystal deposition may induce granuloma formation by stimulating loc al expression of macrophage migration inhibitory factor (MIF), which is a k nown mediator of delayed type hypersensitivity (DTH). Materials and Methods: A model of acute uric acid nephropathy was induced i n rats by the administration of oxonic acid (an inhibitor of uricase), toge ther with uric acid supplements. MIF expression and local cellular response were examined by in situ hybridization and immunohistochemistry. Results: Kidney tissue examined at 35 days posttreatment showed widespread tubulointerstitial damage with intratubular uric acid crystal deposition an d granuloma formation. Tubules within the areas of granuloma showed a six-f old increase in MIF mRNA, compared with uninvolved areas by in situ hybridi zation. Moreover, the areas of increased MIF mRNA expression correlated wit h sites of dense accumulation of macrophages and T cells, and these cells w ere activated when assessed by the expression of interleukin-2R (IL-2R) and (MHC) class II. Interestingly, cytoplasmic staining for MIF protein in the uric acid (UA) crystal-associated granulomatous lesions was reduced, indic ating a rapid MIF secretion by damaged tubules and macrophages secondary to uric acid crystal stimulation. This was confirmed by the demonstration of a marked increase in urinary MIF protein by Western blot analysis. Control rats fed either a normal diet or only oxonic acid had no discernible eviden ce of renal disease by routine light microscopy and minimal tubular express ion of MIF mRNA and protein. Conclusions: These data suggest that intrarenal granulomas in urate nephrop athy may be the consequence of a crystal induced DTH reaction mediated by M IF.