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

Abstract

ABSTRACTBackgroundPharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) 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.MethodsFemaleLrp2f/f mice were bred with maleNdrg1-Cre ERT2+/0 mice to develop PTC-LRP2 +/+ and -/- littermates. To study atherosclerosis, all mice were to bred to an LDL receptor -/- background and fed a Western diet to induce atherosclerosis.ResultsPTC-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 the 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 hypercholesterolemia. By contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney.ConclusionsPTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.HighlightsDeletion of megalin specifically in S1 and S2 of PTCs (proximal tubules) does not reduce atherosclerosis in hypercholesterolemic mice, irrespective of sex.Deletion of megalin in S1 and S2 of PTCs induces TIN (tubulointerstitial nephritis) with severe renal pathological changes in male mice.PTC-specific megalin deficiency-induced TIN occurs in both male LDL receptor -/- and LDL receptor +/+ mice fed a Wetsern diet.The consumption of a Western diet exerts a crucial role in triggerring the observed TIN in male mice with PTC-specific megalin deletion.