Renal Proximal Tubule Cell-Specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed a Western Diet

Background: Pharmacological inhibition of megalin (also known as LRP2 [low-density lipoprotein receptor-related protein-2]) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice. Methods: Female Lrp2 f/f mice were bred with male Ndrg1-Cre ERT2 +/0 mice to develop PTC-LRP2 +/+ and PTC-LRP2 -/- littermates. To study atherosclerosis, all mice were bred to an LDL (low-density lipoprotein) receptor -/- background and fed a Western diet to induce atherosclerosis. Results: PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed a Western diet but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not on hypercholesterolemia. In contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished ALB (albumin) accumulation in PTCs within 10 days of Western diet feeding. RNA-sequencing analyses demonstrated the upregulation of inflammation-related pathways in the kidney. Conclusions: PTC-specific megalin deletion does not affect atherosclerosis but leads to tubulointerstitial nephritis in mice fed a Western diet, with severe pathologies in male mice.