Abstract: SA-PO702
A Kidney-Specific Fasting-Mimicking Diet Induces Podocyte Reprogramming and Restores Kidney Function in Glomerulopathy
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | 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
- Hou, Xiaogang, Children's Hospital Los Angeles, Los Angeles, California, United States
- Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Monji, Sean P., Children's Hospital Los Angeles, Los Angeles, California, United States
- Buono, Roberta, University of California Irvine, Irvine, 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 Division of Nephrology, Seattle, Washington, United States
- Shankland, Stuart J., University of Washington Division of Nephrology, Seattle, Washington, United States
- Lemley, Kevin V., Children's Hospital Los Angeles, Los Angeles, California, United States
- De Filippo, Roger E., 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 chronic kidney disease (CKD) patients. Yet no dietary intervention has shown glomerular regeneration. Cycles of a fasting-mimicking diet (FMD) were previously shown to promote regeneration and reduce damage in the pancreas, blood, gut, and nervous systems but its effect in glomerulopathies are yet unknown.
Methods
We applied cycles of a low-salt FMD (LS-FMD) to puromycin aminonucleoside-induced nephrotic (PAN) rats and monitored renal function and performed histological analysis. We performed qPCR arrays on whole glomeruli and whole kidney snRNA seq during one cycle of LS-FMD and refeeding. Alport syndrome (AS)-FUCCI (Fluorescence Ubiquitin Cell Cycle Indicator) mice were fed with FMD and used to track the cell cycle specifically in podocytes. To determine whether parietal epithelial cells (PECs) contribute to the replacement of podocytes, inducible dual transgenic PEC-Podo mice that lineage trace PECs (red) and podocytes (green) simultaneously were fed LS-FMD following adriamycin-induced nephropathy. To translate these findings, 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 other physiological parameters up to 1 year post treatment.
Results
Cycles of a LS-FMD lowered proteinuria, and restored nephron structure and function in PAN rats. LS-FMD induced the expression of nephrogenic markers, mimicking kidney developmental processes in multiple kidney structures. Specifically in the glomerulus, LS-FMD prevented podocyte loss by preventing entrance to G1/S phase, in addition to activating PEC-podocyte-lineage reprogramming, 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 and improved endothelial function.
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 inflammation and glomerulosclerosis.
Funding
- Private Foundation Support