There are several significant and novel findings shown in this study: (1) PTC-specific deletion of megalin resulted in TIN in male mice fed a Western diet, but not in mice fed a normal laboratory diet, (2) Western diet-induced TIN in PTC-LRP2 −/− mice was independent of hypercholesterolemia, (3) PTC-specific megalin deletion-induced TIN was severe in male mice, but not evident in female mice, and (4) PTC-specific megalin deletion resulted in rapid onset of interstitial inflammation and fibrosis following the initiation of Western diet feeding. Here, LRP2 is linked to familial hypercholesterolemia.