Deletion of Megalin in Kidney Tubular Epithelium Up-Regulates TGFβ1 Signaling, Aggravates Ischemia/Reperfusion Kidney Injury, and Accelerates the Progression to Chronic Kidney Disease.

Ischemic acute kidney injury may accelerate the progression to end-stage renal disease. Megalin has been shown to shuttle stanniocalcin (STC)-1 (which promotes mitochondrial antioxidant defenses) to the mitochondria through the retrograde-early endosomes-to-Golgi pathway; knockout of megalin in cultured cells has been reported to impair glycolysis and mitochondrial respiration. This study sought to determine kidney phenotype after ischemia/reperfusion (I/R) kidney injury in mice with tubular epithelium-specific deletion of megalin. Mice (on C57BL/6 background) with conditional tubular epithelium-specific knockout of megalin (tLrp2KO) and mice with combined conditional tubular epithelium-specific knockout of megalin and overexpression of STC1 (tLrp2KO;tSTC1O) were subjected to ischemia (clamping of renal pedicles), followed by reperfusion for 1, 3, 10, 45, and 90 days. Serum creatinine was measured and kidneys were harvested for analysis. After I/R and compared with control mice, tLrp2KO mice displayed worse acute kidney injury, severe and persistent inflammation, diminished tubular epithelial cell proliferation, up-regulation of TGFβ1 signaling, fibrosis, and accelerated progression to chronic kidney disease. Kidney injury was not rescued in tLrp2KO;tSTC1O mice, consistent with megalin-dependent renal protection by STC1. Freshly isolated proximal tubule fragments from tLrp2KO mice or cultured proximal tubule epithelial cells with megalin knockout displayed activation of TGFβ1 signaling, consistent with modulation of TGFβ1 signaling by megalin. In conclusion, tubular epithelium-specific deletion of megalin aggravates I/R kidney injury, up-regulates TGFβ1 signaling, and accelerates chronic kidney disease progression.