Transforming growth factor-β isoforms and glomerular injury in nephrotoxic nephritis

Background. Transforming growth factor-beta has three main isoforms (TGF-beta 1, TGF-beta 2, and TGF-beta 3) that have distinct but overlapping functions in immunity, inflammation, and tissue repair. TGF-beta 1 has been implicated in progressive renal scarring, but the roles of TGF-beta 2 and TGF-beta 3 are less clear. The purpose of this study was to characterize the expression of all three isoforms in nephrotoxic nephritis (NTN) in rats and to determine the effect of TGF-beta 3 infusions on injury because of its reported combined anti-inflammatory and antifibrotic effects. Methods. TGF-beta 1,TGF-beta 2, and TGF-beta 3 expression was analyzed by immunohistochemistry and RNase protection assays. TGF-beta 3 was administered by osmotic minipumps at 2 mu g/day, a dose shown to alter glomerular macrophage function in vivo. Injury was assessed morphologically and functionally. Results. The three TGF-beta isoforms showed a different distribution in normal rats and after the induction of nephritis. TGF-beta 1 was only detected in glomeruli of the most severely nephritic rats. TGF-beta 2 was found in glomerular neutrophils, whereas damaged podocytes expressed TGF-beta 3. Infusions of TGF-beta 3 did not reduce proteinuria over seven days after the induction of nephritis. They did, however, have a profound effect on glomerular macrophage number (7.76 +/- 4.1 in treated rats vs. 14.4 +/- 4.7 in controls, P < 0.02). The numbers of class II-positive macrophages were similar in the two groups, whereas class II-negative macrophages infiltrating glomeruli were significantly decreased (4.06 +/- 3.1 vs. 9.1 +/- 4.4, P < 0.02). TGF-beta did not influence the amount of glomerular matrix. Conclusions. TGF-beta isoforms have different expressions and presumptively different roles in NTN. The infusion of pharmacological doses of TGF-beta 3 has profound effects on macrophages infiltrating nephritic glomeruli and reveals marked heterogeneity of infiltrating macrophages.