Effects of altered megalin expression on regulation of 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 more profound effects on transcription, suggesting additional roles for megalin in maintaining PT function. We also recently discovered 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. Several studies have associated Lrp2 polymorphisms predicted to alter expression levels with increased risk of chronic kidney disease. To study how alterations in megalin expression impacts and regulates 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 with no apparent change in megalin endocytic rates or half-life. We also found that mitochondrial respiratory capacity, measured by Oroboros, was reduced in both the Lrp2+/- and Lrp2 KO cells compared to the parental OK cells. Current and future studies will focus on understanding how reduced megalin expression affects transcription and cell metabolism and the consequences to disease progression. This abstract was presented at the American Physiology Summit 2026 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.