Kidney Week

Abstract: FR-PO0112

Glyceric Acid as a Metabolic Signature of Proximal Tubular Damage Induced by APOL1-G1 Variant

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Yoshida, Teruhiko, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo, Tokyo, Japan

Teruhiko Yoshida, MD, PhD

• Miyoshi, Tetsushi, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo, Tokyo, Japan

Tetsushi Miyoshi

• Overdahl, Kirsten E., National Institute of Environmental Health Sciences, Durham, North Carolina, United States

Kirsten E. Overdahl, PhD

• Jarmusch, Alan, National Institute of Environmental Health Sciences, Durham, North Carolina, United States

Alan Jarmusch, PhD

• Sweetwyne, Mariya T., University of Washington, Seattle, Washington, United States

Mariya T. Sweetwyne, PhD

• Rosenberg, Avi Z., Johns Hopkins Medicine, Baltimore, Maryland, United States

Avi Z. Rosenberg, MD, PhD, FASN

• Hoofnagle, Andrew N., University of Washington, Seattle, Washington, United States

Andrew N. Hoofnagle, MD, PhD

• Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Jeffrey B. Kopp, MD, FASN

• Kurano, Makoto, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo, Tokyo, Japan

Makoto Kurano, MD, PhD

Background

Progressive tubular injury is common in APOL1 nephropathy, in addition to glomerular damage. The underlying mechanism and metabolic signatures of tubular injury in APOL1 nephropathy remain poorly understood.

Methods

Untargeted metabolomics of kidney tissue and urine, and bulk RNA-seq of kidneys from BAC/APOL1-G0 and -G1 mice systemically expressing APOL1 was conducted 24 hours after intravenous administration of interferon-γ. HK-2 human kidney cells were cultured in conditioned media from HepG2 human liver cells transfected with APOL1 expression vectors to test the effect of plasma APOL1 exposure in vitro. Single-nucleus RNA-seq analysis of kidneys from a nephrotic model in Alb/APOL1 mice, expressing APOL1 only in liver and plasma, was also conducted, and findings were confirmed in the KPMP single-cell tissue atlas.

Results

Metabolomics revealed elevated glyceric acid levels in the kidney and urine of BAC/APOL1-G1 mice, relative to APOL1-G0 mice (Figure). Transcriptomics confirmed that the gene encoding glycerate kinase (Glyctk), which catabolizes glyceric acid, was downregulated in BAC/APOL1-G1 mouse kidneys. Exposure to conditioned media from HepG2 expressing APOL1-G1 reduced HK-2 cell viability. Culture with glyceric acid worsened the viability of HK-2 cells with GLYCTK knockdown. Albuminuria of the BAC/APOL1-G1 mouse interferon-γ model worsened with administration of glyceric acid. Single-nucleus RNA-seq data from the Alb/APOL1 nephrotic mouse showed mitochondrial dysfunction and reduced Glyctk expression in proximal tubular cells of G1 mice relative to wild-type and G0 mice. Human single-cell RNA-seq data (KPMP) showed reduced Glyctk expression in proximal tubule epithelial cells from subjects with AKI and CKD compared with healthy subjects.

Conclusion

Reduced GLYCTK expression and increased glyceric acid could be early metabolic signatures of proximal tubular injury in the setting of APOL1 nephropathy.

Figure: Volcano plots of metabolomics analysis results, comparing BAC/APOL1-G1 vs G0 mice

Funding

• NIDDK Support