Abstract: FR-PO0179
Targeting Sox9-Positive Cells for Redifferentiation Therapy
Session Information
- AKI: Mechanisms - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Moriyama, Tomofumi, Department of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Sugahara, Sho, Division of Diabetology, Endocrinology, and Nephrology, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
- Taguchi, Kensei, Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
- Takenaka, Yuto, Department of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Takahashi, Keiko, Department of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Clouthier, Kelly, Department of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Elias, Bertha C., Department of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Brooks, Craig R., Department of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Acute kidney injury (AKI) is a significant clinical complication that results in a four-fold increase in mortality and predisposes patients to the development of chronic kidney disease (CKD) through the AKI to CKD transition. This transition is primarily driven by injured proximal tubule cells (PTCs) that fail to recover, remaining in a maladaptive state of dedifferentiation, often characterized by the expression of Sox9, a marker of progenitor-like cells and failed repair. In this study, we investigate whether targeting these Sox9-positive, maladaptively repaired PTCs to enhance their mitochondrial health can induce redifferentiation and halt the progression of CKD.
Methods
In vitro, maladaptive repair was induced in LLC-PK1 cells using aristolochic acid (AA). In vivo, AKI to CKD transition was modeled in male C57BL/6 mice by AA administration. To improve mitochondrial function and induce redifferentiation, we administered the mitochondrial fusion promoter M1 or genetically deleted Drp1 in Sox9-positive cells using tamoxifen-inducible Sox9-CreERT2 mice (Drp1ΔSox9PT). Redifferentiation, fibrosis, and dedifferentiation markers were assessed via immunofluorescence, protein, and mRNA analyses. Mitochondrial morphology in kidney was examined using super-resolution microscopy.
Results
Analysis of mitochondrial morphology in vivo and in vitro demonstrated that maladaptively repaired cells, including Sox9-positive PTCs, exhibit pathological mitochondrial fragmentation. In vitro, M1 treatment reversed AA-induced dedifferentiation markers. Crucially, in vivo, targeting Sox9-positive cells through either M1 treatment or Drp1ΔSox9PT reversed mitochondrial fragmentation. This intervention in Sox9-positive cells led to decreased expression of dedifferentiation markers and promoted their redifferentiation. Remarkably, this redifferentiation therapy targeting Sox9-positive cells halted the advancement of CKD and reduced kidney fibrosis.
Conclusion
These results suggest that targeting Sox9-positive, maladaptively repaired PTCs by improving mitochondrial health promotes their redifferentiation, reverses maladaptive repair, and ultimately prevents CKD progression. Future redifferentiation therapies aimed at enhancing mitochondrial function specifically in Sox9-positive injured cells hold promise for preventing the AKI to CKD transition.
Funding
- NIDDK Support