Notch4 activation aggravates NF-kappa B mediated inflammation in HIV-1 associated Nephropathy

Abstract

Notch 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.

Deletion of delta‐like 1 homologue accelerates renal inflammation by modulating the Th17 immune response

“…Studies done in Notch3 ‐deficient mice with the UUO model found less tubular injury and significantly reduced interstitial collagen deposition 38,43,44 . Similarly, Notch2‐ and Notch4‐ deficient mice are protected from several renal‐related injuries, such as folic‐acid or immunodeficiency virus‐associated nephropathy 39,45 . In our study, total NOTCH2 and NOTCH4 receptor protein levels are decreased in Dlk1 ‐null mice as compared to WT, indicating that this could be an effect of Dlk1 deletion or of concomitant Dlk2 overexpression.…”

“…38,43,44 Similarly, Notch2-and Notch4-deficient mice are protected from several renal-related injuries, such as folic-acid or immunodeficiency virus-associated nephropathy. 39,45 In our study, total NOTCH2 and NOTCH4 receptor protein levels are decreased in Dlk1-null mice as compared to WT, indicating that this could be an effect of Dlk1 deletion or of concomitant Dlk2 overexpression. Recent findings indicate that both DLK1 and DLK2 can modulate the activity of the four NOTCH receptors, 46,47 albeit in a different manner.…”

“…Several studies have evaluated the levels of the NOTCH pathway components in experimental and human renal diseases [13][14][15][16][17]38,39 ; however, data about non-canonical NOTCH ligands are scarce. NOTCH ligands and receptors are expressed in a wide range of renal diseases, including membranous nephritis, lupus glomerulonephritis, IgA nephropathy, and diabetic nephropathy.…”

HIV-1 Infection Transcriptomics: Meta-Analysis of CD4+ T Cells Gene Expression Profiles

“…An important aspect of this process concerns the immunological synapses that occur between neighboring cells. We identified the upregulation of Notch pathway-related genes ROBO1, DLL4, DLL1, GATA2, JAG1 and MDK (GO:0007219 “Notch signaling pathway”), which act as co-activators in the stimulation of the NF-κB pathway, which induces IL-2 production, responsible for proliferation and activation of CD4+ T lymphocytes and is associated with latency suppression mechanisms and initiation of viral transcription [ 42 , 47 ]. The NF-κB (nuclear factor kappa B) pathway is exploited by HIV-1 to activate its transcription, by having NF-κB binding sites in its long terminal repeats (LTRs) [ 48 ].…”

LncRNA MIR4435‑2HG inhibits the progression of osteoarthritis through miR‑510‑3p sponging

“…NF-κB signaling is a key regulator in multiple diseases ( 44 , 45 ). NF-κB is an evolutionarily conserved transcription factor that controls the expression levels of various cytokines and adhesion molecules, and is involved in responses to infection, stress and damage ( 46 ).…”