HIV-1 Upregulates VEGF in Podocytes

Reduction of Stat3 Activity Attenuates HIV-Induced Kidney Injury

“…However, semaphorin 3A, a negative regulator of VEGF activation, is significantly downregulated in Tg26 kidney as shown previously. 13 Therefore, we believe that the combination of VEGF upregulation and semaphoring 3A downregulation in Tg26 leads to a highly activated VEGF signaling pathway and contributes to the pathogenesis of HIVAN in these mice.…”

“…23 We recently found that Stat3 mediates HIVinduced HIF2␣ and VEGF expression in podocytes. 13 Therefore, we determined the level of VEGF expression in these mice. By immunostaining, VEGF expression increased significantly in Tg26-SA/ϩ, but not in Tg26-SA/Ϫ mice, compared with their littermates ( Figure 5A, A-D).…”

“…Recently, we found that HIF2␣ and vascular endothelial growth factor (VEGF) are highly upregulated by Nef through activation of Stat3. 13 These findings clearly show that Nef induces an abnormal podocyte phenotype by activating distinct cell signaling pathways in which Stat3 is a key mediator. Furthermore, our previous microarray studies suggest that HIV infection activates IL-6, which is a known activator of the Jak-Stat3 pathway, in kidney tubular cells.…”

Genetic susceptibility to HIV-associated nephropathy

“…The identification of mutations in genes that are expressed by podocytes has explained the cause of a number of Mendelian glomerular diseases (8)(9)(10)(11)(12)(13) and has placed the podocyte in a central position in studies of glomerular disease. In patients with HIVAN, direct HIV-1 infection of podocytes has been documented, and viral proteins induce podocyte proliferation, loss of cell contact inhibition, and upregulation of growth factors in immortalized podocytes in culture (14)(15)(16)(17). The concept of a dysregulated podocyte phenotype in HIVAN has been proposed (15), and this phenotype is characterized by loss of expression of many genes typically seen in differentiated podocytes, such as synaptopodin (SYNPO), nephrosis 1 homolog (NPHS1; which encodes the slit-diaphragm protein nephrin), and NPHS2 (which encodes the podocyte slit diaphragm protein podocin), and with the re-expression of embryonic genes such as paired box gene 2 (PAX2) that are normally only expressed in presumptive podocytes and podocyte progenitors during glomerular development.…”

What Type of VEGF Do You Need?

“…A cursory survey of the literature quickly dismisses this notion. Overexpression of an isoform of VEGF (VEGF164) in murine podocytes during renal development promotes features seen in HIV-associated collapsing FSGS, 6,8 possibly in a Stat3-dependent manner. 9 Induced overexpression of VEGF164 in podocytes of adult mice results in rapid and widespread diabetic nephropathy-like glomerular injury with proteinuria, glomerulomegaly, glomerular basement membrane thickening, mesangial expansion, and podocyte foot process effacement with loss of slit diaphragms.…”