Abstract: SA-PO320
Differential Pathogenic Roles of Notch4 and Notch3 in the Progression of HIV Associated Nephropathy
Session Information
- Cellular Crosstalk in Glomerular Diseases - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Idowu, Jessica Y., University of Kansas Medical Center, Kansas, Kansas, United States
- Home, Trisha, University of Kansas Medical Centre, Kansas City, Kansas, United States
- Singhal, Pravin C., North Shore LIJ Health System, Great Neck, New York, United States
- Fields, Timothy A., University of Kansas Medical Center, Kansas, Kansas, United States
- Sharma, Madhulika, University of Kansas Medical Center, Kansas, Kansas, United States
Background
Notch pathway activation plays a central role in pathogenesis of many glomerular diseases. We have previously shown that Notch 4 and Notch 3 were up-regulated in various renal cells in HIV associated Nephropathy (HIVAN) patients and rodent models of HIVAN. Notch inhibition by gamma secretase inhibitors ameliorated disease progression in the Tg26 mouse model of HIVAN. Since gamma secretase inhibitors are associated with toxicity in clinics, here we explore individual effects of genetic inhibition of Notch4 and Notch3 on HIVAN pathogenesis.
Methods
Tg26 mice were bred with mice deleted for the intracellular domain of Notch 4 and Notch 3 separately to generate Tg26 mice with homozygous Notch4 deletion and homozygous Notch3 deletion, respectively. The effect of Notch4 and Notch3 deletion in Tg26 mice was determined by analyzing renal function, histology, cell proliferation/ podocyte differentiation and inflammatory markers.
Results
Deletion of either Notch 4 or Notch 3 in Tg26 mice significantly decreased the mortality rate and reduced kidney injury in Tg26 mice. While, Notch 4 deletion in male Tg26 mice reduced kidney injury, controlled cell proliferation, cell differentiation and inflammatory response of NF kappa B positive cells in Tg26 mice, it was not enough to significantly reduce proteinuria and blood urea nitrogen (BUN) levels. In contrast, genetic depletion of Notch3 appeared to be effective in a broader way, controlling proteinuria and BUN in Tg26 mice. In addition, histological studies indicated a significant improvement in kidney injury as evident by the reduction in glomerulosclerosis, tubule-interstitial fibrosis and interstitial inflammation in Notch3 deleted Tg26 mice. More studies are underway to reveal subtle roles of Notch4 and Notch3 activation in HIVAN.
Conclusion
Our study supports a non-redundant role of Notch 4 and Notch 3 in HIVAN pathogenesis and suggests therapeutic implications of Notch3 and Notch 4 inhibition in HIV associated nephropathy.
Funding
- NIDDK Support