Notch signaling has shown to play a key role in several kidney diseases, associated with glomerulosclerosis and podocyte apoptosis. However, its role in Human Immunodeficiency Virus Associated Nephropathy (HIVAN) which presents with collapsing variant of glomerulosclerosis, focal segmental glomerulosclerosis, and podocyte/parietal cell proliferation is not known. We used HIVAN patients and rodent models of HIVAN that express seven of the nine HIV genes and phenocopy most characteristics of HIVAN. We show that in contrast to other glomerular diseases, where Notch 1 and Notch2 receptor activation is predominant, Notch 4 pathway appeared to be most predominating in HIVAN. We found activated Notch4 expressed and elevated in podocytes, parietal epithelial cells and tubular epithelium. Pharmacological inhibition of Notch pathway in vivo ameliorated the disease progression in the Tg26 mice. Moreover podocyte proliferation induced by HIV proteins was inhibited by Notch inhibitors. These studies suggest that aberrant Notch signaling, contributes to the pathogenesis of HIVAN. In the first aim, we will determine the effects of podocyte and parietal cell specific genetic inhibition of Notch signaling on disease severity in Tg26 mice. In the second aim, we will perform in vitro studies from podocytes derived from Tg26 mice to determine the effect of Notch inhibition on podocyte proliferation, differentiation and apoptosis. We will also use parietal epithelial cells and podocytes to evaluate the possibility of interaction of Notch proteins with HIV-1 proteins. Finally in the third aim, we will genetically knockdown Notch4 in Tg26 mice and the possibility of disease prevention will be determined. These studies will provide: 1) a mechanism of Notch activation by HIV-1 and 2) a therapeutic platform to test Notch inhibitors in HIVAN patients.

Public Health Relevance

HIV associated nephropathy (HIVAN) presents with distinct tubular and glomerular abnormalities. Disrupted Notch signaling is a key feature of most glomerular diseases, however, we have shown that Notch signaling is differentially activated in HIVAN. The overall objective of this study is to determine the mechanism of Notch activation in HIVAN and whether inhibition of Notch signaling is a therapeutic approach for the treatment of HIVAN. We will use kidney epithelial cells to determine the mechanism of Notch activation and develop HIV-1 animal models with Notch pathway deletion to test our hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK108433-04
Application #
9545765
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Kimmel, Paul
Project Start
2015-09-15
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Silva, Luciane M; Jacobs, Damon T; Allard, Bailey A et al. (2018) Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells. Sci Rep 8:4985
Ward, Christopher J; Sharma, Madhulika (2015) Polycystic Kidney Disease: Lessons Learned from Caenorhabditis elegans Mating Behavior. Curr Biol 25:R1168-70