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dc.contributor.authorPuri, Rajni Vaid
dc.contributor.authorYerrathota, Sireesha
dc.contributor.authorHome, Trisha
dc.contributor.authorIdowu, Jessica Y.
dc.contributor.authorChakravarthi, V. Praveen
dc.contributor.authorWard, Christopher J.
dc.contributor.authorSinghal, Pravin C.
dc.contributor.authorVanden Heuvel, Gregory B.
dc.contributor.authorFields, Timothy A.
dc.contributor.authorSharma, Madhulika
dc.identifier.citationRajni Vaid Puri, Sireesha Yerrathota, Trisha Home, Jessica Y. Idowu, V. Praveen Chakravarthi, Christopher J. Ward, Pravin C. Singhal, Gregory B. Vanden Heuvel, Timothy A. Fields, Madhulika Sharma; Disease Models & Mechanisms 2019 12: dmm040642 doi: 10.1242/dmm.040642 Published 17 December 2019en_US
dc.descriptionA grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see
dc.description.abstractNotch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various renal cells in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) patients and rodent models of HIVAN. In this study, we examined whether the Notch pathway can be distinctly activated by HIV-1 gene products and whether Notch4, in particular, can influence disease progression. Using luciferase reporter assays, we did not observe activation of the NOTCH4 promoter with the HIV protein Nef in podocytes. Further, we observed upregulated expression of a gamma secretase complex protein, presenilin 1, but not Notch4, in podocytes infected with an HIV-1 expression construct. To assess the effects of Notch4 on HIVAN disease progression, we engineered Tg26 mice with global deletion of the Notch4 intracellular domain (Notch4dl), which is required for signaling function. These mice (Notch4d1/Tg26+) showed a significant improvement in renal function and a significant decrease in mortality compared to Tg26 mice. Histological examination of kidneys showed that Notch4d1/Tg26+ mice had overall glomerular, tubulointerstitial injury and a marked decrease in interstitial inflammation. A significant decrease in the proliferating cells was observed in the tubulointerstitial compartments of Notch4d1/Tg26+ mice. Consistent with the diminished inflammation, kidneys from Notch4d1/Tg26+ mice also showed a significant decrease in expression of the inflammatory cytokine transcripts Il-6 and Ccl2, as well as the master inflammatory transcription factor NF-κB (Nfkb1 transcripts and p65 protein). These data identify Notch4 as an important mediator of tubulointerstitial injury and inflammation in HIVAN and a potential therapeutic target.en_US
dc.description.sponsorshipNational Institutes of Health (R01DK108433 awarded to M.S.)en_US
dc.publisherThe Company of Biologistsen_US
dc.rights© 2019. Published by The Company of Biologists Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.titleNotch4 activation aggravates NF-κB-mediated inflammation in HIV-1-associated nephropathyen_US
kusw.kuauthorPuri, Rajni Vaid
kusw.kuauthorYerrathota, Sireesha
kusw.kuauthorHome, Trisha
kusw.kuauthorIdowu, Jessica Y.
kusw.kuauthorChakravarthi, V. Praveen
kusw.kuauthorWard, Christopher J.
kusw.kuauthorFields, Timothy A.
kusw.kuauthorSharma, Madhulika
kusw.kudepartmentInternal Medicineen_US
kusw.kudepartmentThe Jared Grantham Kidney Instituteen_US
kusw.kudepartmentPathology and Laboratory Medicineen_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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© 2019. Published by The Company of Biologists Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License.
Except where otherwise noted, this item's license is described as: © 2019. Published by The Company of Biologists Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License.