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

Autor:	Amioka N; Saha Cardiovascular Research Center and Saha Aortic Center., Franklin MK; Saha Cardiovascular Research Center and Saha Aortic Center., Kukida M; Saha Cardiovascular Research Center and Saha Aortic Center., Zhu L; Saha Cardiovascular Research Center and Saha Aortic Center., Moorleghen JJ; Saha Cardiovascular Research Center and Saha Aortic Center., Howatt DA; Saha Cardiovascular Research Center and Saha Aortic Center., Katsumata Y; Sanders-Brown Center on Aging.; Department of Biostatistics., Mullick AE; Ionis Pharmaceuticals, Carlsbad, California, USA., Yanagita M; Department of Nephrology, Kyoto University Graduate School of Medicine.; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan., Martinez-Irizarry MM; Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Sandoval RM Jr; Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Dunn KW; Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Sawada H; Saha Cardiovascular Research Center and Saha Aortic Center.; Department of Physiology, University of Kentucky, Lexington, Kentucky, USA., Daugherty A; Saha Cardiovascular Research Center and Saha Aortic Center.; Department of Physiology, University of Kentucky, Lexington, Kentucky, USA., Lu HS; Saha Cardiovascular Research Center and Saha Aortic Center.; Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 27. Date of Electronic Publication: 2024 Sep 27.
DOI:	10.1101/2024.05.11.592234
Abstrakt:	Background: 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), 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 -/- littermates. To study atherosclerosis, all mice were bred to an LDL 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 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. In 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. Conclusions: PTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.
Databáze:	MEDLINE
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