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The homophilic adhesion molecule sidekick-1 contributes to augmented podocyte aggregation in HIV-associated nephropathy

Lewis Kaufman^*,1, Guozhe Yang^*, Kayo Hayashi^*,, James R. Ashby^*, Li Huang^*, Michael J. Ross^*, Mary E. Klotman and Paul E. Klotman^*

^* Division of Nephrology and

Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York, USA; and

Division of Nephrology, Juntendo University School of Medicine, Tokyo, Japan

¹Correspondence: Mt. Sinai School of Medicine, Division of Nephrology, Box 1243, One Gustave L. Levy Pl., New York, NY, USA 10029. E-mail: lewis.kaufman{at}mssm.edu

The collapsing glomerulopathy of HIV-associated nephropathy (HIVAN) is characterized by podocyte dedifferentiation and proliferation. In affected glomeruli, proliferating podocytes adhere in aggregates to form glomerular pseudocrescents and fill an enlarged Bowman’s space. Previously, we reported that sidekick-1 (sdk-1), an adhesion molecule of the immunoglobulin superfamily, was highly up-regulated in HIV-1 transgenic podocytes. In the current work, we explore how sdk-1 overexpression contributes to HIVAN pathogenesis. Murine podocytes infected with HIV-1 virus expressed significantly more sdk-1 than control-infected cells. Podocytes stably transfected with an sdk-1 expression construct grew in large aggregates with a simplified morphology characterized by a disorganized actin cytoskeleton, changes similar to podocytes in HIVAN. In contrast to controls, HIV-1 infected podocytes adhered to stably transfected sdk-1 podocyte aggregates in mixing studies. Furthermore, substrate-released cell sheets of wild-type podocytes were readily dissociated by mechanical stress, whereas HIV-1 podocytes remained in aggregates. The number of HIV-1 podocyte aggregates was significantly reduced in cells expressing a short hairpin RNA (shRNA) construct specific for sdk-1 compared with cells expressing control shRNA. Finally, in a HIVAN mouse model, sdk-1 protein was detected in podocytes in collapsed glomerular tufts and in glomerular pseudocrescents. These findings suggest that sdk-1 is an important mediator of cellular adhesion in HIV-infected podocytes and may contribute to podocyte clustering that is characteristic of pseudocrescent formation in HIVAN.—Kaufman, L., Yang, G., Hayashi, K., Ashby, J.R., Huang, L., Ross, M.J., Klotman, M.E., Klotman, P.E. The homophilic adhesion molecule sidekick-1 contributes to augmented podocyte aggregation in HIV-associated nephropathy.

Key Words: HIVAN • pseudocrescent • collapsing glomerulopathy