Abstract: SA-PO792
HIV-1 Protein Nef Acts in Synergy with APOL1-G1 to Impair Nephrocyte Function by Inhibiting Autophagy and Endocytosis Pathway
Session Information
- Genetic Diseases: Glomerulopathies - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Author
- Zhu, Junyi, University of Maryland Baltimore, Baltimore, Maryland, United States
Background
Individuals carrying APOL1 risk alleles G1 and G2 have higher chances of developing HIV-associated nephropathy (HIVAN). The role of APOL1 in HIVAN is mostly derived from studies done in cultured renal cells or clinical genetic studies. However, very little is known about how APOL1 risk alleles and HIV-1 genes interact in vivo to induce HIVAN. The basic mechanisms responsible for the synergistic renal pathological effects of APOL1 risk alleles and HIV-1 are still unclear.
Methods
Because Drosophila nephrocyte, is remarkably similar, both structurally and functionally, to the mammalian podocyte, here we generated transgenic flies selectively expressing APOL1 nephropathy risk Alleles G1 and HIV-1 protein Nef in Drosophila nephrocytes. We then investigated the structural and functional effects on the fly nephrocytes.
Results
As transgenic flies with APOL1-G1 aged, we found nephrocyte function declined, cell size increased, the structure of the slit diaphragms defected, and nephrocytes died prematurely. Furthermore, we showed that the expression of APOL1-G1 impaired the nephrocyte function by affecting the acidification of organelles by inhibiting the endocytosis pathway. Next, we noticed that the expression of HIV-1 protein Nef facilitated these nephrocyte impairments. We further found that expressing of HIV-1 protein Nef in nephrocytes induced the accumulation of autophagosomes and inhibited the autophagy pathway, which facilitated the impairments of the acidification of organelles, and functional structure of nephrocytes.
Conclusion
These results suggested that Nef and APOL1-G1 lead to the increased risk of renal failure through their synergistic regulation of the autophagy and endocytosis pathway, which will provide new therapeutic targets to prevent HIV-associated nephropathy.
Funding
- NIDDK Support