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Activation of Notch signaling pathway in HIV-associated nephropathy

Sharma, Madhulikaa,*; Callen, Shannonb; Zhang, Dac; Singhal, Pravin Cd; Vanden Heuvel, Gregory Ba,*; Buch, Shilpab,*

doi: 10.1097/QAD.0b013e32833dbc31
Basic Science

Objective: HIV-associated nephropathy (HIVAN) is characterized by the development of glomerulosclerosis and is associated with glomerular epithelial cell proliferation. It has recently been shown that activation of the Notch signaling pathway in podocytes results in glomerulosclerosis and podocyte proliferation. To determine whether Notch signaling is involved in renal disorder associated with HIVAN, we evaluated the expression of Notch receptors in HIVAN.

Design: We evaluated the expression of the Notch signaling pathway using an HIV-transgenic (HIV-Tg) rat model of HIVAN, and biopsy samples from HIVAN and normal controls.

Methods: Paraffin sections and kidney lysates were used for immunohistochemistry, immunofluorescence and western blot analysis.

Results: A collapsing variant of glomerulosclerosis and focal segmental sclerosis was observed in HIV-Tg rats. Glomeruli of HIV-Tg rats demonstrated activation of Notch1 and Notch4, as determined by the presence of the intracellular domains. In addition, we observed increased expression of the Notch target protein, hairy enhancer of split homolog-1 in glomeruli of these animals. The expression of the Groucho homolog transducin-like enhancer protein 4, a Notch effector protein, and the homeodomain protein cut homeobox 1 were also significantly increased in glomeruli of HIV-Tg rats, and this was associated with decreased expression of the cyclin kinase inhibitor p27. Intriguingly, renal biopsy samples from HIVAN patients also showed upregulation of cleaved Notch1 and Notch4 in the glomeruli compared with the expression in normal kidneys.

Conclusion: Our results demonstrate activation of Notch signaling pathway in HIVAN, thereby underscoring its role in disease pathogenesis.

aDepartment of Anatomy and Cell Biology and The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA

bDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA

cDepartment of Pathology, University of Kansas Medical Center, Kansas City, Kansas, USA

dDepartment of Medicine, Division of Kidney Diseases and Hypertension, North Shore Long Island Jewish Health System, New Hyde Park, New York, USA.

*M.S., S.B. and G.B.V.H. contributed equally to the writing of this article.

Received 11 February, 2010

Revised 17 June, 2010

Accepted 30 June, 2010

Correspondence to Madhulika Sharma, PhD, Department of Anatomy and Cell Biology and The Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA. Tel: +1 913 588 0713; fax: +1 913 588 2710; e-mail: msharma3@kumc.edu

© 2010 Lippincott Williams & Wilkins, Inc.