Kidney Week

Abstract: TH-PO0232

Proximal Tubular ALOX5 Links Extracellular Matrix Homeostasis and Collagen Remodeling in Renal Fibrosis

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Moon, Youngyoon, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Youngyoon Moon, MD, MS

• Lim, Hyun Ji, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Hyun Ji Lim, MS

• Hwang-Bo, Jeon, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Jeon Hwang-Bo, PhD

• Lee, Tae Hoon, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Tae Hoon Lee, PhD

• Jung, Su Woong, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Su Woong Jung, MD, PhD

• Kim, Yang Gyun, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Yang Gyun Kim, MD

• Lee, Sang ho, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Sang ho Lee

• Moon, Ju young, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Ju young Moon, MD, PhD

Background

Renal fibrosis, a common histopathologic feature of chronic kidney disease, is characterized by excessive matrix accumulation caused by dysregulated of extracellular matrix (ECM) turnover. Arachidonate 5-lipoxygenase (ALOX5), a key enzyme in leukotriene biosynthesis, plays crucial roles in inflammatory cell recruitment and immune activation. Proximal tubule is the primary site where renal fibrosis begins after injury. Among ALOX5-derived leukotrienes, leukotriene D4 (LTD4) is a potent mediator acting through the cysteinyl leukotriene receptors expressed in tubular epithelial cells. However, the contribution of proximal tubular Alox5 to collagen deposition and ECM remodeling during renal fibrosis remains unclear.

Methods

Tamoxifen-inducible proximal tubule-specific Alox5 knockout mice were subjected to unilateral ureteral obstruction. Renal fibrosis, epithelial integrity, ECM remodeling, and immune activation were assessed by histological, immunohistochemical, imaging, molecular and biochemical analyses. HKC-8 cells were stimulated with Alox5-derived metabolites or TGF-β1, while Alox5 activity was inhibited by zileuton or siRNA silencing. Immune activation was further evaluated using CD11c-YFP mice and a THP-1 co-culture system in vitro.

Results

Proximal tubular Alox5 deletion markedly reduced tubulointerstitial fibrosis and preserved epithelial integrity in UUO kidneys, with decreased expression of CCL2, CXCL12 collagen I, and collagen III. Second Harmonic Generation and Fluorescence-Lifetime Imaging Microscopy imaging revealed that Alox5 deficiency preserved ECM organization and reduced collagen compaction. In vitro, LTD4 and 5-HETE increased total soluble collagen and inflammatory mediators, whereas pharmacologic or genetic inhibition of Alox5 attenuated these responses. Monocyte adhesion and avidity to HKC-8 cells were also reduced by Alox5 inhibition, and 3D imaging of CD11c-YFP kidneys showed decreased immune cell infiltration.

Conclusion

Proximal tubular epithelial Alox5 acts as a critical mediator linking inflammation and immune activation to structural remodeling during tubulointerstitial fibrosis. Alox5 blockade attenuates fibrosis by suppressing immune activation and inflammatory signaling, restoring ECM homeostasis, and reducing fibrotic collagen accumulation. These findings suggest that proximal tubule-specific Alox5 may serve as a promising upstream therapeutic target for renal fibrosis.