Increased levels of transforming growth factor-β in HIV-associated nephropathy

Abstract

Background. Human immunodeficiency virus-associated nephropathy (HIVAN) is a renal disease of unknown pathogenesis. Recent evidence suggests that the fibrogenic cytokine transforming growth factor-β (TGF-β) might be involved. We hypothesized that overproduction of TGF-β in the kidney might be involved in the pathogenesis of HIVAN. Methods. The mRNA and protein expression of TGF-β isoforms, TGF-β1, TGF-β2, and TGFβ3, deposition of matrix proteins induced by TGF-β, and levels of HIV Tat protein were studied in HIVAN. Controls included normal and diseased kidneys from HIV-positive and - negative patients. The ability of Tat to induce production of TGF-β and matrix proteins was also studied in human mesangial cells. Results. Normal kidneys, thin basement membrane nephropathy, and minimal change disease were negative for the three TGF-β isoforms and Tat. In HIVAN, levels of TGF-β isoforms and Tat were significantly increased, along with the expression of TGF-β mRNA and deposition of matrix proteins stimulated by TGF-β. Increased levels of TGF-β isoforms, but not Tat, were also found in other glomerular diseases characterized by matrix accumulation. HIV infection, in the absence of HIVAN, was not associated with an increase in TGF-β or Tat expression. Tat stimulated the expression and production of TGF-β1 and matrix proteins by human mesangial cells. Conclusions. Our findings suggest that overproduction of TGF-β is involved in the pathogenesis of HIVAN.