Abstract: FR-PO0183
Overexpression of Megalin in Kidney Tubular Epithelium Protects from Ischemia-Reperfusion (I/R) Kidney Injury; Sustained Overexpression of Megalin After I/R Induces Clonal Hematopoiesis
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
- Li, Qingtian, Baylor College of Medicine, Houston, Texas, United States
- Sheikh-Hamad, David (Daud), Baylor College of Medicine, Houston, Texas, United States
Background
Ischemic AKI may accelerate the progression to end-stage kidney disease (ESKD). We have recently shown megalin shuttles the mitochondrial intracrines STC1, Angiotensin II and TGF-β1 from the cell surface to the mitochondria. Within the mitochondria, megalin associates with STC1 and SIRT3, which are known to promote anti-oxidant defenses. We have also shown deletion of megalin impairs glycolysis and mitochondrial respiration, and deletion of megalin in tubular epithelial cells aggravates ischemia/reperfusion kidney injury and accelerates the progression to CKD. In the current work, we sought to determine whether overexpression of megalin in tubular epithelial cells protects from I/R kidney injury.
Methods
We generated mice (on C57B/6 background) with conditional tubular epithelium-specific overexpression of megalin (referred to herein as tLrp2OE). Eight to twelve weeks old mice were subjected to bilateral renal ischemia/reperfusion (clamping of renal pedicles for 30 minutes followed by reperfusion). Mice were euthanized after 1, 3, 10, 45 and 90 days, serum creatinine was measured and kidneys were harvested for analyses.
Results
Compared with control mice, tLrp2OE mice demonstrated preservation of kidney morphology, lower serum creatinine and less kidney injury after I/R through day 10; however, sustained overexpression of megalin after I/R leads to clonal hematopoiesis and decline in kidney function at the later time points (day 45 and day 90).
Conclusion
Tubular epithelium-specific overexpression of megalin protects from I/R kidney injury. However, sustained overexpression of megalin after I/R kidney injury, may be deleterious.
Funding
- Veterans Affairs Support