Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

Pharmacological 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), PTC-LRP2 +/+ and −/− littermates in an LDL receptor −/− background were generated and fed a Western diet to determine effects of PTC- derived megalin on atherosclerosis. 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 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. Overall, PTC- specific megalin deletion leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice. ### Competing Interest Statement Adam E. Mullick is an employee of Ionis Pharmaceuticals, Inc. Motoko Yanagita has received research grants from Mitsubishi Tanabe Pharma and Boehringer Ingelheim. The other authors have declared that no conflict of interest exists. * AngII : angiotensin II ASO : antisense oligonucleotides LDL : low-density lipoprotein LRP2 : low-density lipoprotein receptor-related protein 2 PTC : proximal tubule cell