TCF7/MiR-802-5p promotes delayed graft function in cold-storage kidney transplantation by inducing mitochondrial...

Area of Science:

• Nephrology
• Molecular Biology
• Transplantation Immunology

Background:

• Cold storage and reperfusion injury are major causes of acute tubular injury and delayed graft function (DGF) after kidney transplantation.
• The precise mechanisms by which these stresses lead to mitochondrial dysfunction remain incompletely understood.

Purpose of the Study:

• To identify the molecular pathways linking cold storage to mitochondrial collapse in renal tubules.
• To investigate the role of microRNAs in mediating cold storage-associated kidney injury.
• To explore potential diagnostic and therapeutic targets for improving kidney transplant outcomes.

Main Methods:

• Utilized a cold storage-associated kidney transplantation (CST) mouse model with tubule-specific Dicer deletion.
• Performed miRNA profiling to identify differentially expressed microRNAs.
• Investigated the direct targets and regulatory mechanisms of key microRNAs using luciferase assays and Western blotting.
• Assessed mitochondrial integrity, tubular injury, and graft function.
• Measured urinary and intrarenal miR-802-5p levels in kidney transplant recipients with and without DGF.

Main Results:

• Dicer deletion in renal tubules protected against CST-induced mitochondrial ultrastructural damage, tubular injury, and improved graft function.
• miR-802-5p was identified as a Dicer-processed microRNA induced by CST, crucial for mediating Dicer loss-associated protection.
• miR-802-5p directly targets IMMT (mitofilin), a mitochondrial cristae organizer, leading to reduced IMMT expression, disrupted cristae, and impaired respiration.
• Overexpression of IMMT restored mitochondrial function and mitigated graft injury.
• The Wnt effector TCF7 activates miR-802-5p transcription; TCF7 inhibition reduced miR-802-5p induction and protected against CST damage.
• Elevated urinary and intrarenal miR-802-5p levels correlated with DGF and impaired graft function in human kidney transplant recipients.

Conclusions:

• A TCF7-Dicer-miR-802-5p-IMMT axis links cold storage to mitochondrial stress and kidney transplant injury.
• miR-802-5p is a key mediator of mitochondrial dysfunction and graft damage following cold storage.
• This pathway represents a promising diagnostic biomarker and therapeutic target for preventing DGF and improving kidney allograft survival.