Deletion of Megalin in Kidney Tubular Epithelium Upregulates Transforming Growth Factor (TGF)β1 Signaling, Aggravates Ischemia-Reperfusion Kidney Injury, and Accelerates Progression to CKD

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Background: Ischemic acute kidney injury (AKI) may accelerate the progression to end-stage kidney disease (ESKD). We have shown stanniocalcin-1 (STC1) promotes mitochondrial anti-oxidant defenses and confers resistance to ischemia/reperfusion (I/R) kidney injury. We have also shown STC1 is shuttled by megalin 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. Methods: We generated mice (on C57B/6 background) with conditional tubular epithelium-specific knock-out (KO) of megalin (referred to herein as tLrp2KO) and mice with combined conditional tubular epithelium-specific KO of megalin and overexpression of STC1 (referred to as tLrp2KO;tSTC1O). Eight to twelve weeks old mice were subjected to 30 minutes kidney ischemia (clamping of renal pedicles) 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 I/R in control mice, I/R in tLrp2KO mice displayed worse AKI, characterized by severe and persistent inflammation (through day 90), diminished tubular epithelial cell proliferation, upregulation of TGFβ1 signaling, fibrosis and accelerated progression to chronic kidney disease (CKD). Kidney injury was less severe in female mice; however, I/R injury was greater in female tLrp2KO mice compared with control. Kidney injury was not rescued in tLrp2KO;tSTC1O mice, consistent with megalin-dependent STC1-mediated renal protection from I/R. Knockout of megalin as shown in freshly-isolated proximal tubule fragments from tLrp2KO mice or CRISPR-Cas9-mediated gene editing in cultured proximal tubule epithelial cells (BUMPT) is associated with activation of TGFβ1 signaling, consistent with modulation of TGFβ1 signaling by megalin. Conclusion: Tubular epithelium-specific deletion of megalin aggravates I/R kidney injury, upregulates TGFβ1 signaling and accelerates the progression to CKD. Funding: Veterans Affairs Support

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