Kidney Week

Abstract: TH-PO0298

Podocyte-Derived LOXL2 Promotes Albuminuria and NLRP3 Inflammasome Priming in Diabetic Kidney Disease

Session Information

• Glomerular Diseases: Cell Biology
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Choi, Hoon Young, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea (the Republic of)

Hoon Young Choi, MD, PhD

• Jeon, Nara, Gangnam Severance Hospital, Seoul, Gangnamgu, Korea (the Republic of)

Nara Jeon

• Lim, Beom Jin, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea (the Republic of)

Beom Jin Lim, MD, PhD

Background

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide, and podocyte dysfunction is central to its progression. Although NLRP3 inflammasome activation is increasingly recognized as a key driver of DKD, the mechanisms that trigger podocyte inflammasome activation under metabolic stress remain poorly defined.

Methods

CRISPR/Cas9-mediated LOXL2 knockout human podocytes were exposed to high glucose (HG) and lipopolysaccharide (LPS) to assess cytoskeletal integrity and NLRP3 inflammasome signaling. Podocyte-specific LOXL2 conditional knockout mice (Nphs2-Cre; Loxl2^flox/flox, LOXL2^KO-Pod) were subjected to streptozotocin (STZ) administration and a high-fat diet (HFD). Podocyte structure, renal inflammasome signaling, albuminuria, and kidney injury were evaluated in vitro and in vivo.

Results

LOXL2 expression was elevated in glomeruli from DKD patients on Nephroseq database. In human podocytes, HG and LPS induced LOXL2 upregulation, while CRISPR/Cas9-mediated knockout abolished this induction (>85% reduction; P<0.001). LOXL2 deletion preserved synaptopodin expression and attenuated HG/LPS-induced upregulation of NLRP3, caspase-1, and IL-1β mRNA and protein.
In podocyte-specific LOXL2 knockout mice (LOXL2KO-Pod; Nphs2-Cre; Loxl2flox/flox) subjected to STZ and/or HFD, renal NLRP3 and caspase-1 induction was significantly attenuated compared to PodCre controls. Immunofluorescence confirmed reduced glomerular LOXL2 and preserved synaptopodin expression. Despite comparable body weight and blood glucose, LOXL2KO-Pod mice showed markedly reduced urinary albumin-to-creatinine ratio (P<0.001). LOXL2 deletion also decreased α-SMA expression, reduced F4/80-positive macrophage infiltration, and preserved WT-1-positive podocyte number in diabetic kidneys.

Conclusion

Podocyte-derived LOXL2 promotes diabetic kidney disease by contributing to podocyte injury and NLRP3 inflammasome priming. Targeting LOXL2 may represent a therapeutic strategy to modulate sterile inflammation and preserve the glomerular filtration barrier in diabetic kidney disease.