Abstract: TH-PO0379
RBP-J Functions as a Transcriptional Repressor of HIV-LTR in Podocytes and Protects Against HIV-Associated CKD
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Wang, Wei, The University of Kansas Medical Center, Kansas City, Kansas, United States
- Sommer, Nicole, The University of Kansas Medical Center, Kansas City, Kansas, United States
- Gier, Owen, The University of Kansas Medical Center, Kansas City, Kansas, United States
- Placide, Sagine, The University of Kansas Medical Center, Kansas City, Kansas, United States
- Diaz-Rocha, Ashley, The University of Kansas Medical Center, Kansas City, Kansas, United States
- Sharma, Madhulika, The University of Kansas Medical Center, Kansas City, Kansas, United States
Background
RBP-J acts as both a transcriptional repressor and activator of Notch signaling. Notch activation is implicated in several glomerular diseases, and podocyte-specific RBP-J deletion improves renal injury in these models. We previously showed that Notch signaling is activated in kidneys from HIV-associated chronic kidney disease (HIV-CKD) patients and HIV-CKD mouse model (Tg26), and that Notch inhibition reduces disease progression. However, RBP-J has also been reported to physically bind the HIV-LTR promoter and suppress HIV gene transcription. Since HIV-CKD severity depends on renal HIV expression, we hypothesized that podocyte-specific deletion of RBP-J may relieve HIV-LTR repression and worsen disease progression via activating the HIV-LTR.
Methods
Tg26, RBP-J floxed, and podocin-Cre mice were crossed to generate podocyte-specific RBP-J knockout mice in the Tg26 background (Tg-RBP-J-PodKO). Wild-type, Tg26, and Tg-RBP-J-PodKO littermates (n=6–10/group) were compared. Kidney weight/body weight (KW/BW) ratio, renal histology, serum albumin levels, and HIV Nef expression were evaluated. Luciferase reporter assays were performed in cultured podocytes to assess the effects of RBP-J inhibition on HIV-LTR transcription. DAPT was used to inhibit Notch signaling, while RIN1 was used to disrupt RBP-J-mediated transcription.
Results
Tg-RBP-J-PodKO mice exhibited increased KW/BW ratios and developed more severe tubulointerstitial injury, tubular dilation with protein casts, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Serum albumin levels were significantly reduced in Tg-RBP-J-PodKO mice, consistent with increased albuminuria. In addition, Nef expression was markedly elevated in Tg-RBP-J-PodKO kidneys compared with Tg26 controls. In cultured podocytes, when Notch signaling was inhibited by DAPT, additional RBP-J inhibition with RIN1 significantly increased HIV-LTR luciferase activity, suggesting that RBP-J functions as a transcriptional repressor of HIV-LTR.
Conclusion
Podocyte-specific deletion of RBP-J worsens HIV-CKD in Tg26 mice with increased HIV gene expression. Pharmacologic disruption of RBP-J repressor complexes also enhances HIV-LTR transcription in podocytes. These findings suggest that, in addition to its role in Notch signaling, RBP-J suppresses HIV transcription in podocytes and protects against HIV-CKD.
Funding
- Other U.S. Government Support