Effects of reduced megalin expression on proximal tubule function

The proximal tubule (PT) of the kidney is comprised of cells that are uniquely specialized for efficient recovery of essentially all of the filtered glucose, amino acids, and protein that escapes the glomerular filtration barrier. The multiligand receptor megalin ( Lrp2 ) drives apical endocytic activity in PT cells. Knockout (KO) of megalin or the adaptor protein Dab2 have similar effects on endocytic uptake, however Lrp2 KO has greater effects on transcription and metabolism, suggesting additional roles for megalin in maintaining PT function. Consistent with an effect on metabolism, we recently reported that Lrp2 KO in mice conferred increased glucose tolerance but sensitized mice to western diet-induced kidney injury [Youm et al. 2024 Function]. Megalin expression varies in disease conditions, and the effects of intermediate reductions in megalin are complex and not well understood. Two large studies of genetic variants reached divergent conclusions- one study found predicted haploinsufficiency or hypomorphic expression of megalin associated with lower risk of kidney disease, while the other observed a correlation with reduced eGFR and increased BUN. To study how reduced megalin expression impacts PT function, we knocked out one allele of Lrp2 in opossum kidney (OK) cells to generate a haploinsufficient ( Lrp2 +/- ) cell model. Uptake of the megalin ligand myoglobin was reduced in Lrp2 +/- cells, however albumin uptake mediated by cubilin was unaffected. Energy utilization measured by Oroboros of both the Lrp2 +/- and Lrp2 KO cells revealed impaired energy utilization when compared to the parental OK cells. By contrast, no changes in energy utilization were observed in Dab2 KO cells. Future studies will focus on understanding how reduced megalin expression affects transcription, cell metabolism, and the response to high fat and high sugar diets. U54 DK137329, R01 DK125049 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.