Hypoxia-inducible Factor-1α Suppresses the Innate Immune Response in Cultured Human Proximal Tubular Cells

Overview

Journal In Vivo

Specialty Oncology

Date 2023 Oct 31

PMID 37905653

Authors

Daiki Nagawa

Michiko Shimada

Masamichi Nakata

Ikuyo Narita-Kinjo

Takeshi Fujita

Reiichi Murakami

Norio Nakamura

Hirofumi Tomita

Affiliations

Soon will be listed here.

Abstract

Background/aim: Retinoic acid-inducible gene (RIG)-I like receptors (RLRs) are expressed on renal proximal tubular epithelial cells (RPTECs) in viral nephropathy, indicating the presence of RLR-mediated innate immune responses in RPTECs. Hypoxia is also known to affect innate immunity. This study investigated the effects of hypoxia, and hypoxia-inducible factor (HIF) on innate immunity in RPTECs.

Materials And Methods: Primary human RPTECs were cultured under normoxic or hypoxic conditions and treated with a synthetic analog of double-stranded RNA (polyIC). The expression levels of RIG-I and MDA5, as RLRs, and IFNβ, IL6, and TNFα, as inflammatory mediators were evaluated using quantitative reverse transcription-polymerase chain reaction, western blotting, and lactate dehydrogenase activity (LDH) assays. To further investigate the role of hypoxia, a small interfering RNA was used to knockdown HIF1α.

Results: Under normoxic conditions, polyIC increased RIG-I, MDA5, and IFNβ mRNA expression in RPTECs by, 9.4±0.4-, 10.8±0.5-, and 4.0±0.1-fold, respectively, compared to control, and by 5.4±0.1-, 7.4±0.1-, and 2.4±0.3-fold, respectively, under hypoxic conditions, the rate of increase was lower than that under normoxic conditions (p<0.01). Protein expression showed a similar trend. Under hypoxic conditions, polyIC treatment with HIF1α knockdown in RPTECs increased RIG-I, MDA5, and IFNβ mRNA expression by 3.1±0.5-, 2.9±0.4-, and 6.1±0.4-fold, respectively, and cytotoxicity, demonstrated by LDH assay, was increased compared to that without knockdown (all p<0.01).

Conclusion: Hypoxia suppresses polyIC-induced RLRs mediated innate immune responses in RPTECs via HIF1α.

Citing Articles

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Muller A, Lozoya M, Chen X, Weissig V, Nourbakhsh M Biomedicines. 2023; 11(12).

PMID: 38137543 PMC: 10741437. DOI: 10.3390/biomedicines11123322.

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