Kidney Week

Abstract: SA-OR26

Promotion of Mitochondrial Recovery Prevents Proximal Tubular Cell Maladaptive Repair and AKI-to-CKD Transition

Session Information

• CKD: New Insights into Mechanisms and Treatment Strategies
  October 26, 2024 | Location: Room 24, Convention Center
  Abstract Time: 05:40 PM - 05:50 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Sugahara, Sho, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Sho Sugahara, MD, PhD

• Moriyama, Tomofumi, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Tomofumi Moriyama, MD, PhD

• Taguchi, Kensei, Kurume Daigaku Igakubu Daigakuin Igaku Kenkyuka, Kurume, Fukuoka, Japan

Kensei Taguchi, MD, PhD

• Elias, Bertha C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Bertha C. Elias, PhD

• Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Craig R. Brooks, PhD

Background

Acute kidney injury (AKI) is a major clinical complication which results in a four-fold increase in mortality and predisposes patients to developing chronic kidney disease (CKD) through the AKI-to-CKD transition. Following AKI, the transition to CKD is largely driven by injured proximal tubule cells that fail to recover from injury and remain in a state of maladaptive dedifferentiation termed maladaptive repair. Here, we study whether improving the mitochondrial health of maladaptively repaired PTCs can prevent CKD progression.

Methods

In vitro, maladaptive repair was induced by treatment of LLC-PK1 cells with aristolochic acid (AA). In vivo, AKI-to-CKD transition was induced by administration of AA to 8-12 weeks old male BL57Bl/6 (WT) mice. Mitochondrial morphology was improved by pharmacological administration of the mitochondrial fusion promoter M1 or genetic deletion of Drp1 under the control of the inducible Pax8 promotor (Drp1^ΔPT). Fibrosis and dedifferentiation markers were measured by immunofluorescence, protein expression and mRNA levels. Mitochondrial function was analyzed using Seahorse analyzer. Mitochondrial morphology was measured by super-resolution microscopy.

Results

In vivo and in vitro analysis of mitochondrial morphology revealed that maladaptively repaired cells have shorter and smaller mitochondria, indicating pathological mitochondrial fragmentation. In vitro, reversing mitochondrial fragmentation with M1 improves mitochondrial function and increases expression of mitochondrial fatty acid oxidation (FAO) genes. The increased mitochondrial function not only prevents maladaptive repair, but it also promotes redifferentiation of cells already in the maladaptively repaired state. In vivo, pharmacological treatment with M1 or deletion of Drp1 reverses the mitochondrial fragmentation, which is associated increased expression of mitochondrial FAO genes. Remarkably, improving mitochondrial morphology/function also induces redifferentiation of maladaptively repaired cells and halts progression of CKD and kidney fibrosis.

Conclusion

These data indicate that promoting mitochondrial recovery improves mitochondrial health, reverses PTC maladaptive repair, and ultimately prevents CKD progression. Future therapeutics targeting mitochondrial fragmentation have the potential to prevent AKI-to-CKD transition.

Funding

• Private Foundation Support