Circulating Fibroblast Growth Factor-2, HIV-Tat, and Vascular Endothelial Cell Growth Factor-A in HIV-Infected Children with Renal Disease Activate Rho-A and Src in Cultured Renal Endothelial Cells.
Renal endothelial cells (REc) are the first target of HIV-1 in the kidney. The integrity of REc is maintained at least partially by heparin binding growth factors that bind to heparan sulfate proteoglycans located on their cell surface. However, previous studies showed that the accumulation of two heparin-binding growth factors, Vascular Endothelial Cell Growth Factor-A (VEGF-A) and Fibroblast Growth Factor-2 (FGF-2), in combination with the viral protein Tat, can precipitate the progression of HIV-renal diseases. Nonetheless, very little is known about how these factors affect the behavior of REc in HIV+ children. We carried out this study to determine how VEGF-A, FGF-2, and HIV-Tat, modulate the cytoskeletal structure and permeability of cultured REc, identify key signaling pathways involved in this process, and develop a functional REc assay to detect HIV+ children affected by these changes. We found that VEGF-A and FGF-2, acting in synergy with HIV-Tat and heparin, affected the cytoskeletal structure and permeability of REc through changes in Rho-A, Src, and Rac-1 activity. Furthermore, urine samples from HIV+ children with renal diseases, showed high levels of VEGF-A and FGF-2, and induced similar changes in cultured REc and podocytes. These findings suggest that FGF-2, VEGF-A, and HIV-Tat, may affect the glomerular filtration barrier in HIV+ children through the induction of synergistic changes in Rho-A and Src activity. Further studies are needed to define the clinical value of the REc assay described in this study to identify HIV+ children exposed to circulating factors that may induce glomerular injury through similar mechanisms.
Center for Genetic Medicine Research, Children's National Health Systems, Washington DC, United States of America.
Jharna R
JR
Das
Department of Pharmacology, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
J Silvio
JS
Gutkind
Center for Genetic Medicine Research, Children's National Health Systems, Washington DC, United States of America.|Division of Nephrology, Children's National Health Systems, Washington DC, United States of America.|Department of Pediatrics, The George Washington University, Washington DC, United States of America.
Patricio E
PE
Ray
D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015658:HIV Infections / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000652:urine; D015497:HIV-1 / Q000502:physiology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D010539:Permeability / Q000187:drug effects; D050199:Podocytes / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2; D006493:Heparin; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein