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Renal tubular cell binding of β-catenin to TCF1 versus FoxO1 is associated with chronic interstitial fibrosis in transplanted kidneys
- Source :
- American Journal of Transplantation. 21:727-739
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- β-Catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of β-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. β-Catenin/FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation. and inflammatory fibrosis (P < .001). The relative binding of β-catenin/TCF1 versus β-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at 1 year (n = 131, all P < .001). The TF ratio was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717), and moderate fibrosis (AUC 0.769) using receiver operating characteristic analysis. An independent validation cohort (n = 76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% vs. 2.6%, P = .047), however, not with other outcomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of β-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.
- Subjects :
- Pathology
medicine.medical_specialty
Tubular atrophy
Inflammation
Proximity ligation assay
030230 surgery
Kidney
03 medical and health sciences
0302 clinical medicine
Fibrosis
Humans
Immunology and Allergy
Medicine
Pharmacology (medical)
Hepatocyte Nuclear Factor 1-alpha
beta Catenin
Kidney transplantation
Transplantation
Proteinuria
Forkhead Box Protein O1
business.industry
Epithelial Cells
medicine.disease
Kidney Tubules
Catenin
Biomarker (medicine)
Kidney Diseases
medicine.symptom
business
Subjects
Details
- ISSN :
- 16006135
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- American Journal of Transplantation
- Accession number :
- edsair.doi.dedup.....285ac56aa83c5af0aaa8918a342e280b