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

Abstract

Background. Transforming growth factor-β has three main isoforms (TGF- β1, TGF-β2, and TGF-β3) that have distinct but overlapping functions in immunity, inflammation, and tissue repair. TGF-β1 has been implicated in progressive renal scarring, but the roles of TGF-β2 and TGF-β3 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-β3 infusions on injury because of its reported combined anti- inflammatory and anti-fibrotic effects. Methods. TGF-β1, TGF-β2, and TGF- β3 expression was analyzed by immunohistochemistry and RNase protection assays. TGF-β3 was administered by osmotic minipumps at 2 μg/day, a dose shown to alter glomerular macrophage function in vivo. Injury was assessed morphologically and functionally. Results. The three TGF-β isoforms showed a different distribution in normal rats and after the induction of nephritis. TGF-β1 was only detected in glomeruli of the most severely nephritic rats. TGF-β2 was found in glomerular neutrophils, whereas damaged podocytes expressed TGF-β3. Infusions of TGF-β3 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 us. 9.1 ± 4.4, P < 0.02). TGF-β did not influence the amount of glomerular matrix. Conclusions. TGF-β isoforms have different expressions and presumptively different roles in NTN. The infusion of pharmacological doses of TGF-β3 has profound effects on macrophages infiltrating nephritic glomeruli and reveals marked heterogeneity of infiltrating macrophages.