Sex-dependent impairment of kidney function in megalin knockout mice

Megalin ( Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. We previously found that knocking out Lrp2 in the opossum kidney (OK) PT cell line leads to differential expression of genes involved in mitochondrial and metabolic function. Additionally, we observed large reductions in sodium glucose co-transporter 2 (Sglt2) transcript (>80%) and protein (~40%) expression levels. While Sglt2 transcript and protein levels in Lrp2 KO in mice were more modestly reduced, male and female KO mice fed regular chow or a Western diet (WD) had increased tolerance to a high glucose challenge compared with control mice. Surprisingly, male Lrp2 KO mice fed a WD developed substantial kidney injury, while female KO mice had significantly less injury. In metabolic studies, Lrp2 KO mice preferentially utilized fatty acid oxidation compared to control mice. We hypothesize that compromised endocytic flux in Lrp2 KO mice impairs mitochondrial and metabolic function to worsen kidney damage in a sex-dependent manner. Current studies are focused on a variety of approaches to test how reduced endocytic capacity impacts mitochondrial function and metabolism in Lrp2 KO cells and control OK cells. We will confirm our findings in age-matched male and female control and Lrp2 KO mice. These studies will help to determine the role of megalin expression and function on PT metabolism, function, and overall health. National Institutes of Health: T32DK061296, T32AG021885-20, RO1 DK125049, RO1 DK118726, S10 OD028596, U54 DK137329. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.