Abstract: PO0210
Klotho Deficiency Intensifies Hypoxia-Induced Expression of INF-α/β Through Upregulation of Rig-I
Session Information
- AKI Mechanisms - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Urabe, Asako, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan
- Doi, Shigehiro, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan
- Doi, Toshiki, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan
- Nakashima, Ayumu, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan
- Masaki, Takao, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan
Background
Hypoxia is a common pathway to progression of end-stage kidney disease. Although numerous studies have provided evidence that inflammation plays a major role in this process, the mechanism by which hypoxia induces inflammation remains unknown. Retinoic acid-inducible gene-I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for production of interferon (IFN)-α/β to prevent the spread of a viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency intensified the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive.
Methods
In vitro, expression of RIG-I and INF-α/β was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O2) for 30, 60, 90, and 120 min. Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine expression of RIG-I and INF-α/β under hypoxic conditions. In vivo, we induced renal hypoxia by clamping the renal artery for 10 min in wildtype mice (hypoxic WT mice) and Klotho knockout mice (hypoxic Kl-/- mice). Lastly, we investigated the expression levels of RIG-I and INF-α/β in 33 human kidney biopsy samples diagnosed with IgA nephropathy.
Results
In vitro, incubation under hypoxic conditions increased expression of Rig-I and IFN-α/β in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting Rig-I. In vivo, the expression levels of Rig-I and IFN-α/β were upregulated in kidneys of hypoxic WT mice and further upregulation was observed in hypoxic Kl-/- mice. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that expression of Rig-I was correlated with that of IFN-α/β (r=0.57, P＜0.001, and r=0.81, P＜0.001, respectively).
Conclusion
These findings suggest that hypoxia induces expression of INF-α/β through upregulation of Rig-I, and that klotho deficiency intensifies this hypoxia-induced expression.