Podocyte proliferation and de-differentiation are the hallmarks of the collapsing glomerulopathy associatedwith HIV-associated nephropathy (HIVAN). Nef, an HIV-1 accessory protein, was recently found to causepodocyte proliferation and dedifferentiation by activating the STAT3/MAPK1,2 pathways. STAT3 activationrequires tyrosine 705 phosphorylation; however serine 727 phosphorylation increases its transcriptionalactivity. A mouse strain that is wild-type/null (STATS +/-) and a strain with a S727A mutation at the serinephosphorylation site (STATS SA) allows for generation of mice with variable amounts of STATStranscriptional activity (wild type 100%; SA/+ 75%; SA/SA and +/- 50%; SA/- 25%). Using this mouse model,our plan is to study the role of STATS in causing the phenotypic changes of podocytes observed in HIVAN. Different mice strains are known to have variable degrees of susceptibility to renal disease in the setting ofHIV-1 infection. HIV-transgenic mice (Tg26) are on the FBV background and develop more severe renaldisease in response to HIV-1 infection than many other strains of mice. Since STATS knockout mice are onthe C57/B6 background, our secondary goal is to determine if differences exist between the two strains inpodocyte cell proliferation and activation of signaling pathways in response to HIV-1 infection.
