Tubular-Specific Nrf2 Deficiency Exacerbates Inflammation and Metabolic Dysfunction in Early UUO via Distinct Transcriptome Remodeling

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https://storage.unitedwebnetwork.com/files/1099/6a08acaf7f237f12d8dde6532cba174b.pdf

Abstract Title *

Tubular-Specific Nrf2 Deficiency Exacerbates Inflammation and Metabolic Dysfunction in Early UUO via Distinct Transcriptome Remodeling

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Co-author 1

Erika Hishida e-hishida@dokkyomed.ac.jp Dokkyo Medical University Nephrology and Hypertension Tochigi Japan *

Co-author 2

Kazutoshi Ono r1506ok@jichi.ac.jp Jichi Medical University Nephrology Tochigi Japan -

Co-author 3

Tatemitsu Rai t-rai@dokkyomed.ac.jp Dokkyo Medical University Nephrology and Hypertension Tochigi Japan -

Co-author 4

Daisuke Nagata nagatad@jichi.ac.jp Jichi Medical University Nephrology Tochigi Japan -

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Introduction

Nuclear factor erythroid 2-related factor 2 (Nrf2) critically regulates the antioxidant and anti-inflammatory pathways in the kidneys. While its renoprotective effects have been established in chronic kidney disease (CKD), the specific functions of Nrf2 in tubular cells during acute interstitial fibrosis and immune responses remain unclear. This study aimed to delineate the effects of tubular Nrf2 deficiency on transcriptional, metabolic, and phenotypic responses in early unilateral ureteral obstruction (UUO).

Methods

Tubule-specific Nrf2 knockout (Nrf2flox/flox; Pax8Cre+) and control (Nrf2flox/flox) mice underwent UUO. Renal stress and injury were assessed by quantifying Megalin and NGAL mRNA expression on days 3 and 7 and the kidney weight/body weight ratio. Bulk RNA sequencing at day 3 post-UUO revealed differentially expressed genes (DEGs; FDR<0.05), evaluated by Reactome and Gene Ontology (GO) enrichment.

Results

UUO led to time-dependent decreases in the expression of Nrf2 downstream genes, such as Nqo1. This suppression was more pronounced in the kidneys of Nrf2flox/flox; Pax8Cre+ mice compared to those of Nrf2flox/flox controls. Megalin expression decreased on day 3 and NGAL increased on day 7 in both genotypes, but alterations were amplified in Nrf2flox/flox; Pax8Cre+mice. These mice showed a pronounced decrease in the kidney weight/body weight ratio post-UUO, indicating greater parenchymal loss.

Transcriptome analysis showed UUO-induced 346 DEGs in controls, including upregulation of Sox9 (epithelial repair), Fga/Fgg (coagulation), and Spp1 (immune modulation), with Reactome highlights in hemostasis, IGF transport, matrix organization, and complement cascade, and GO terms reflecting immune response and proliferation. In Nrf2flox/flox; Pax8Cre+ mice, 873 DEGs were involved in epithelial turnover (Sprr2f), monocyte chemotaxis (Ccl2), innate immunity (Il1f6), and suppression of anti-inflammatory/metabolic genes (Serpina1d, Ces1f). Pathway analyses indicated strong enrichment in chemokine signaling, immune response, and metabolic process impairment.

Conclusion

Tubular Nrf2 deficiency intensified early UUO-driven inflammation, redox disequilibrium, and metabolic impairment, which were typified by exaggerated chemokine signaling and downregulation of Nrf2-dependent antioxidant and metabolic gene programs. These transcriptomic alterations reflect the failure of Nrf2-governed cytoprotective networks in regulating glutathione synthesis, NADPH regeneration, and lipid detoxification, promoting oxidative and proinflammatory cascades. The dominance of catabolic and inflammatory pathways, together with the loss of detoxifying and biosynthetic functions, identifies Nrf2 as a central integrator of redox and metabolic homeostasis in the tubular epithelium under stress. These mechanistic findings demonstrate that tubular Nrf2 is indispensable for restraining innate immune activation and preserving epithelial metabolic integrity, thereby coupling oxidative stress control with inflammation and nephron resilience in obstructive nephropathy.

This abstract includes data that were previously presented at the 68th Annual Meeting of the Japanese Society of Nephrology. Re-submission of this work to WCN 2026 has been permitted by the organizers of the original meeting.

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