Abstract: FR-PO0780
Kidney-Specific Fasting-Mimicking Diet Induces Podocyte Reprogramming and Restores Kidney Function in Glomerulopathy
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Villani, Valentina, Children's Hospital Los Angeles, Los Angeles, California, United States
- Clair, Geremy, Pacific Northwest National Laboratory, Richland, Washington, United States
- Monji, Sean P., Children's Hospital Los Angeles, Los Angeles, California, United States
- Da Sacco, Stefano, Children's Hospital Los Angeles, Los Angeles, California, United States
- Lai, Silvia, Universita degli Studi di Roma La Sapienza, Rome, Lazio, Italy
- Laviano, Alessandro, Universita degli Studi di Roma La Sapienza, Rome, Lazio, Italy
- Eng, Diana G., University of Washington, Seattle, Washington, United States
- Shankland, Stuart J., University of Washington, Seattle, Washington, United States
- Lemley, Kevin V., Children's Hospital Los Angeles, Los Angeles, California, United States
- Longo, Valter, University of Southern California, Los Angeles, California, United States
- Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
Background
Dietary changes are recommended for CKD patients. Yet no nutritional intervention has shown potential to induce glomerular repair. Here, we studied if a fasting-mimicking diet (FMD) can promote regeneration and reduce damage in glomerulopathy.
Methods
We applied multiple cycles of a low-salts FMD (LS-FMD) to puromycin aminonucleoside-induced nephrotic rats (PAN) and evaluated renal function and morphology. We performed snRNA seq during one cycle of LS-FMD and performed proteomics by LC-MS/MS after both short- and long-term intervention. Alport syndrome mice expressing FUCCI (Fluorescence Ubiquitin Cell Cycle Indicator) under the NPHS2 promoter were used to study how LS-FMD modulates cell cycle in podocytes. To determine if parietal epithelial cells (PECs) contribute to podocyte replacement, inducible dual reporter transgenic PEC-Podo mice, which allow the simultaneous tracing of PECs and podocytes, were fed LS-FMD after adriamycin-induced damage. We also performed a pilot clinical trial on CKD patients receiving three 5-day cycles of the human version of the FMD and monitored renal and multiple physiological parameters up to 1 year post treatment.
Results
Cycles of a LS-FMD significantly lowered proteinuria and restored nephron structure and function in PAN rats. snRNA seq and proteomics analysis indicated that LS-FMD modulated different molecular signaling, including the IGF1/IGF1R and mTOR/FOXO1 cascades, and stimulated developmental processes in multiple kidney structures at the end of one cycle. Proteomic analysis revealed metabolic changes shifting towards fatty acid beta-oxidation short-term. At long-term, LS-FMD induced immunomodulation. LS-FMD reduced podocyte loss by blocking their entry into the G1/S phase of the cell cycle and stabilizing their quiescent state (G0 phase). Furthermore, the LS-FMD induced activation of PEC to podocyte transdifferentiation, as evidenced by lineage tracing studies. In the pilot randomized cross-over study in CKD patients, FMD cycles promoted renoprotection including long-term reduction of proteinuria.
Conclusion
We have developed a dietary intervention with the potential to limit and even reverse kidney damage by preserving the number and function of podocytes and reducing glomerulosclerosis.
Funding
- Private Foundation Support