Recruitment of renal tubular epithelial cells expressing verotoxin-1 (Stx1) receptors in HIV-1 transgenic mice with renal disease.

Abstract

Human immunodeficiency virus (HIV)-infected children are at risk of developing several renal parenchymal diseases, including hemolytic uremic syndrome (HUS). HUS is most frequently caused by infection with enteric Escherichia coli producing Shiga-like toxins (Stxs). In vitro studies have shown that cytokines known to be present at high systemic levels in HIV-1-infected children up-regulate the expression of the Stx glycolipid receptor (Gb3) in cultured endothelial cells. Thus, we studied whether HIV-1 or the HIV-associated "cytokine milieu" could modulate the expression of renal Stxs receptors in vivo. We used HIV-1 transgenic mice (HIV-Tg) expressing a deletion mutant of HIV-1 (pNL4-3). These mice develop renal disease similar to that of HIV-1-infected children. The expression of Gb3 was studied in renal sections from control and HIV-Tg mice by histochemistry, thin layer chromatography overlay studies, and high-pressure liquid chromatography. By histochemistry, we found a significant recruitment of renal tubular epithelial cells expressing Gb3 in HIV-Tg mice with nephropathy, whereas kidneys from control mice showed limited staining in renal tubules. Gb3 was not found in glomeruli of either control or HIV-Tg mice. Thin layer chromatography overlay studies with Stxs and high-pressure liquid chromatography studies confirmed the marked elevation of Gb3 in HIV-Tg kidneys with renal disease. These results suggest that the presence of HIV-associated nephropathy is associated with the recruitment of renal tubular epithelial cells expressing Stx1 receptors. The up-regulation of Stx1 receptors in HIV-diseased kidneys may increase the sensitivity of these cells to the cytotoxic effects of Stxs.