NEPHROPATHY IN HUMAN IMMUNODEFICIENCY VIRUS-1 TRANSGENIC MICE IS DUE TO RENAL TRANSGENE EXPRESSION

HIV-associated nephropathy (HIVAN) is a progressive glomerular and tub ular disease that is increasingly common in AIDS patients and one of t he leading causes of end stage renal disease in African Americans, A m ajor unresolved issue in the pathogenesis of HIVAN is whether the kidn ey disease is due to renal cell infection or a ''bystander'' phenomeno n mediated by systemically dysregulated cytokines. To address this iss ue, we have used two different experimental approaches and an HIV-1 tr ansgenic mouse line that develops a progressive renal disease histolog ically similar to HIVAN in humans, In the murine model, kidney tissue expresses the transgene and in heterozygous adults, renal disease deve lops shortly thereafter, We demonstrate by terminal deoxynucleotide tr ansferase-mediated dUTP-biotin nick-end labeling assay that similar to the disease in humans, apoptosis of renal tubular epithelial cells is a component of the molecular pathogenesis. To determine whether apopt osis is due to transgene expression or environmental factors, we treat ed fetal kidney explants (normal and transgenic) with UV light to indu ce transgene expression Apoptosis occurred in transgenic but not norma l littermates after stimulation of transgene expression, To confirm a direct effect of HIV expression on the production of HIVAN, we transpl anted kidneys between normal and transgenic mice, HIVAN developed in t ransgenic kidneys transplanted into nontransgenic littermates, Normal kidneys remained disease free when transplanted into transgenic litter mates, Thus, the renal disease in the murine model is intrinsic to the kidney. Using two different experimental approaches, we demonstrate a direct effect of transgene expression on the development of HIVAN in the mouse, These studies suggest that in humans, a direct effect of HI V-1 expression is likely the essential cause of HIVAN, rather than an indirect effect of cytokine dysregulation.