HIV-associated nephropathy (HIVAN) is the third leading cause of the end-stage renal disease in African Americans between ages 20-64. One of the pathologic features of HIVAN is collapsing focal segmental glomerulosclerosis (FSGS). Glomerular podocytes, the key cells involved in FSGS, exhibit a disease phenotype characterized by proliferation and dedifferentiation in both human and mouse kidneys with HIVAN. We reported that HIV-1 mRNA were expressed in podocytes of HIVAN patients and of HIV-1 transgenic mice. Studies from transgenic mice suggest that Nef, one of the HIV accessory proteins, plays an important role in the pathogenesis of HIVAN. We found that Nef induces podocyte proliferation and loss of contact inhibition in vitro. In addition, we found that Nef induces podocyte dedifferentiation and the rearrangement of actin filaments. Our preliminary data also suggest that Nef activates Src-Stat3, Ras-MAPK, and Rac1/CDC42 pathways in kidney podocytes. In this study, we propose the following specific aims: 1. To determine in podocytes: a) how Nef induces cell proliferation and loss of contact inhibition by examining the effects of Nef on expressions of cyclins, cyclin inhibitors, integrins, and adhesion molecules; b) how Nef affects the expression of differentiation markers, the organization of actin filaments and microtubules, and the arrangement of actin-associated molecules such as synaptopodin, Ezrin, and CD2AP. 2. To determine in podocytes: a) what are the potential Nef-interactive proteins as well as their down-stream signaling pathways; b) to define the relationships between Nef-induced signaling pathways and Nef-induced phenotypic changes using dominant negative mutants for Src, Stat3, Ras, Rac1/CDC42 or mutants for different Nef binding motifs. 3. To verify that these in vitro findings have in vivo relevance by determining: a) whether Nef induces similar signaling pathways and phenotypic changes in primary cultures of murine podocytes; b) whether these phenotypic changes and signaling pathway activations are observed in kidney podocytes of HIV transgenic mice and HIV patients with HIVAN in vivo. These studies should elucidate essential mechanism responsible for the development of HIV-associated nephropathy and how Nef plays a role in this pathologic process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK065495-02
Application #
6788057
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2003-08-15
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$127,845
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Liu, Ruijie; Zhong, Yifei; Li, Xuezhu et al. (2014) Role of transcription factor acetylation in diabetic kidney disease. Diabetes 63:2440-53
Fan, Ying; Wei, Chengguo; Xiao, Wenzhen et al. (2014) Temporal profile of the renal transcriptome of HIV-1 transgenic mice during disease progression. PLoS One 9:e93019
Li, Xuezhu; Dai, Yan; Chuang, Peter Y et al. (2014) Induction of retinol dehydrogenase 9 expression in podocytes attenuates kidney injury. J Am Soc Nephrol 25:1933-41
Azeloglu, Evren U; Hardy, Simon V; Eungdamrong, Narat John et al. (2014) Interconnected network motifs control podocyte morphology and kidney function. Sci Signal 7:ra12
Potla, Uma; Ni, Jie; Vadaparampil, Justin et al. (2014) Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis-associated glomerular injury. J Clin Invest 124:1757-69
Campbell, Kirk N; He, John C (2014) Can biomarkers of disease activity guide treatment in FSGS? Clin J Am Soc Nephrol 9:1507-9
Dai, Yan; Gu, Leyi; Yuan, Weijie et al. (2013) Podocyte-specific deletion of signal transducer and activator of transcription 3 attenuates nephrotoxic serum-induced glomerulonephritis. Kidney Int 84:950-61
Jiang, Song; Chuang, Peter Y; Liu, Zhi-Hong et al. (2013) The primary glomerulonephritides: a systems biology approach. Nat Rev Nephrol 9:500-12
Jin, Yuanmeng; Ratnam, Krishna; Chuang, Peter Y et al. (2012) A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med 18:580-8
Ma'ayan, Avi; He, John C (2010) Protein kinase target discovery from genome-wide messenger RNA expression profiling. Mt Sinai J Med 77:345-9

Showing the most recent 10 out of 20 publications