We wish to characterize the mechanisms for responsible for focal segmental glomerulosclerosis (FSGS) and use these findings to devise more effective therapy. First, we have investigated the pathogenesis of HIV-associated FSGS. We have studied a mouse transgenic for two HIV accessory proteins, Tat and Vpr, and have found that this mouse develops FSGS. Since Tat mice do not develop kidney disease, we believe that Vpr may be the nephrotoxic protein. Vpr is highly toxic to developing mouse embryos. Therefore, we have recently established transgenic lines which will express Vpr under the control of a tetracycline inducible promoter. Preliminary data suggests abnormalities of mitochondrial structure in the proximal tubular epithelial cells, where the transgene is expressed. Second, we are studying the genetics of FSGS in human patients. We have collected blood and prepared immortalized B cell lines as a source of DNA from 220 African-American patients with FSGS and a control group 215 African Americans infected with HIV but without renal disease. We have initiated candidate gene analysis and have identified significant differences in the ACE and TGF-beta genes between the two groups. Third, we have investigated the possibility that other viruses besides HIV-1 contribute to the pathogenesis of FSGS. We have identified infectious SV40 in the urinary cells of 40% of FSGS patients, 10% of other glomerular disease patients, and 5% of healthy volunteers. These data suggest that either SV40 infections may be relatively common in the healthy population, remain latent in kidney, and are activated by kidney disease, or alternatively that SV40 may play a role in the pathogenesis of kidney disease, including possibly FSGS. We have also identified SV40 infections in patients with polyoma virus nephropathy following renal transplant. Fourth, we have initiated two treatment studies of idiopathic FSGS, using a pilot study design. We are treating patients with newly-diagnosed FSGS with intermittent dexamethasone therapy, and we are treating patients with steroid-resistant FSGS with the anti-fibrotic agent pirfenidone.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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U.S. National Inst Diabetes/Digst/Kidney
United States
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Heymann, Jurgen; Winkler, Cheryl A; Hoek, Maarten et al. (2017) Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte. Nephrol Dial Transplant 32:i65-i70
Okamoto, Koji; Honda, Kenjiro; Doi, Kent et al. (2015) Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney. Am J Pathol 185:1889-98
Lee, Hewang; Abe, Yoshifusa; Lee, Icksoo et al. (2014) Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats. Kidney Int 85:561-9
Cravedi, P; Kopp, J B; Remuzzi, G (2013) Recent progress in the pathophysiology and treatment of FSGS recurrence. Am J Transplant 13:266-74
Abe, Yoshifusa; Sakairi, Toru; Beeson, Craig et al. (2013) TGF-?1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. Am J Physiol Renal Physiol 305:F1477-90
Sharma, Kumar; Ix, Joachim H; Mathew, Anna V et al. (2011) Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 22:1144-51
Wong, Yuen Fei; Kopp, Jeffrey B; Roberts, Catherine et al. (2011) Endogenous retinoic acid activity in principal cells and intercalated cells of mouse collecting duct system. PLoS One 6:e16770
Kopp, Jeffrey B; Winkler, Cheryl A; Nelson, George W (2010) MYH9 genetic variants associated with glomerular disease: what is the role for genetic testing? Semin Nephrol 30:409-17
Genovese, Giulio; Friedman, David J; Ross, Michael D et al. (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841-5
Oleksyk, Taras K; Nelson, George W; An, Ping et al. (2010) Worldwide distribution of the MYH9 kidney disease susceptibility alleles and haplotypes: evidence of historical selection in Africa. PLoS One 5:e11474

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