Activation of Notch signaling pathway in HIV-associated nephropathy.
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.


METHODS
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.


CONCLUSIONS
Our results demonstrate activation of Notch signaling pathway in HIVAN, thereby underscoring its role in disease pathogenesis.
Sharma
Madhulika
M
Department of Anatomy and Cell Biology and The Kidney Institute, University of Kansas Medical Center, Kansas City, USA. msharma3@kumc.edu
Callen
Shannon
S
Zhang
Da
D
Singhal
Pravin C
PC
Vanden Heuvel
Gregory B
GB
Buch
Shilpa
S
D016263:AIDS-Associated Nephropathy / Q000473:pathology*; D000818:Animals; D049109:Cell Proliferation; D015658:HIV Infections / Q000235:genetics / Q000473:pathology*; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000473:pathology*; D050199:Podocytes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D051880:Receptors, Notch