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Kidney Week

Abstract: SA-OR95

Protective Role of RBPjk in HIV-Related CKD

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Sharma, Madhulika, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Sommer, Nicole, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Thornton, Mackenzie, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
Background

The Notch signaling is activated in HIV-associated Nephropathy. The Notch signaling is initiated when a ligand binds to a Notch receptor and leads to cleavage and translocation of the Notch intracellular domain (NICD) into the nucleus. NICD binds to RBPjk and converts it into a transcriptional activator from a repressor and leads to activation of Notch downstream targets. The HIV-LTR promoter contains two RBPjk binding sites. It is thought that RBPjk is a repressor of HIV-LTR. This would imply counterintuitive roles of Notch and RBPjk in HIV-related diseases. Here we investigate for the first time the in vivo roles of RBPjk in regulating the podocyte and myeloid-specific HIV gene expression.

Methods

The Tg26 mice harbor the active HIV-LTR promoter in many cells/tissues. Tg26 mice were bred with floxed RBPjk mice. The resulting mice were further bred with mice harboring podocin-cre or lysM-cre promoters to drive the RBPjk deletion in podocytes or myeloid precursors, respectively. The resulting mice, Tg26: RBPjkKO-Pod or Tg26:RBPjkKO-LysM were compared with normal or Tg26 mice. Renal disease severity was assessed by histology, renal function and inflammation assessment. Nef gene expression served as a measure of HIV-LTR activity.

Results

Deletion of RBPjk alone in podocytes led to disease aggravation and early lethality in Tg26 mice. Compared to Tg26 mice, Tg26:RBPjkKO-Pod mice exhibited increased collapsing glomerular phenotype, focal segmental glomerulosclerosis, blood urea nitrogen, tubular dilations and fibrosis. There was an increase in inflammatory markers IL6 and MMP10. NFkB (p65) was drastically elevated in the glomerular and tubular compartments. RBPjk deletion in podocytes of Tg26 mice did not affect N3ICD expression. Moreover, a significant increase in the nef expression was observed. Similarly Tg26:RBPjkKO-LysM mice had increased disease severity compared to Tg26 mice but less than Tg26:RBPjkKO-Pod mice.

Conclusion

RBPjk deletion in podocytes may be sufficient to activate the HIV-LTR promoter which increases expression of HIV genes leading to inflammation and disease aggravation. This indicates a non-canonical Notch signaling activation and Notch-independent roles of RBPjk in HIV-related diseases. Elucidating these mechanisms are important for treatment strategies and add to our understanding of the latency caused by HIV in people treated with antiretroviral therapy.

Funding

  • NIDDK Support