TY - JOUR
T1 - Activation of Notch signaling pathway in HIV-associated nephropathy
AU - Sharma, Madhulika
AU - Callen, Shannon
AU - Zhang, Da
AU - Singhal, Pravin C.
AU - Vanden Heuvel, Gregory B.
AU - Buch, Shilpa
PY - 2010/9/10
Y1 - 2010/9/10
N2 - 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.
AB - 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.
KW - HIV-associated nephropathy
KW - Notch
KW - cut homeobox 1
KW - glomerulosclerosis
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U2 - 10.1097/QAD.0b013e32833dbc31
DO - 10.1097/QAD.0b013e32833dbc31
M3 - Article
C2 - 20706108
AN - SCOPUS:77956227414
SN - 0269-9370
VL - 24
SP - 2161
EP - 2170
JO - AIDS
JF - AIDS
IS - 14
ER -