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Kidney Week

Abstract: FR-OR17

Tubular Epithelium-Specific Deletion of Megalin Aggravates Ischemia/Reperfusion Kidney Injury and Accelerates the Progression to CKD

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 05:24 PM - 05:33 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Li, Qingtian, Baylor College of Medicine, Houston, Texas, United States
  • Holliday, Michael, Baylor College of Medicine, Houston, Texas, United States
  • Pan, Jenny S., Baylor College of Medicine, Houston, Texas, United States
  • Sheikh-Hamad, David (Daud), Baylor College of Medicine, Houston, Texas, United States

Ischemic AKI may accelerate the progression to ESKD. We have shown stanniocalcin-1 (STC1) activates AMPK and promotes mitochondrial anti-oxidant defenses through upregulation of uncoupling protein 2 and SIRT3. Transgenic overexpression of STC1 confers resistance to ischemia/reperfusion (I/R) kidney injury. We have shown STC1 is shuttled by megalin from the cell surface to the mitochondria through retrograde-early endosomes-to-Golgi- and Rab32-mediated pathway; knockout of megalin in cultured cells impairs glycolysis and mitochondrial respiration. In the current experiments, we sought to determine kidney phenotype after I/R kidney injury in mice with tubular epithelium-specific deletion of megalin.


We generated mice (on C57B/6 background) with tubular epithelium-specific KO of megalin (Lrp2f/f;Pax8rtTA;LC1-Cre; referred to as tLrp2KO) and combined tubular epithelium-specific KO of megalin and overexpression of STC1 (Lrp2f/f;tetOhSTC1;Pax8rtTA;LC1-Cre; referred to as tLrp2KO;tSTC1O), upon treatment with Doxycycline. Eight -12 weeks old mice were subjected to 30 min ischemia (clamping both renal pedicles) followed by reperfusion. Mice were euthanized after 1, 3, 10 and 45 days, blood was collected for creatinine measurement, and kidneys were harvested for analyses.


Compared with I/R in control mice, I/R in tLrp2KO mice was associated with more severe AKI (higher NGAL and serum creatinine), greater inflammation and fibrosis. Kidney injury was less severe in female mice; but, the injury was greater in female tLrp2KO mice. Kidney injury was not rescued in tLrp2KO;tSTC1O mice, consistent with megalin-dependent STC1-mediated renal protection from I/R. I/R in tLrp2KO mice was associated with exaggerated inflammatory response that persisted through day 45, diminished tubular epithelial cell proliferation, upregulation of TGF-ß signaling and fibrosis, and accelerated CKD progression. CRISPR-Cas-mediated knockout of megalin in cultured proximal tubular epithelial cells (BUMPT) upregulates TGF-ß signaling, induces cell cycle arrest, impaires mitogenesis and diminishes autophagosome clearance.


Tubular epithelium-specific deletion of megalin aggravates I/R kidney injury and accelerates the progression to CKD.


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