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, Elynna B Youm Renal-Electrolyte Division Department of Human Genetics, University of Pittsburgh School of Public Health , Pittsburgh, PA , USA Search for other works by this author on: Oxford Academic Katherine E Shipman Renal-Electrolyte Division Search for other works by this author on: Oxford Academic Wafaa N Albalawy Renal-Electrolyte Division Department of Human Genetics, University of Pittsburgh School of Public Health , Pittsburgh, PA , USA Search for other works by this author on: Oxford Academic Amber M Vandevender Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine Search for other works by this author on: Oxford Academic Ian J Sipula Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine Search for other works by this author on: Oxford Academic Youssef Rbaibi Renal-Electrolyte Division Search for other works by this author on: Oxford Academic Allison E Marciszyn Renal-Electrolyte Division Search for other works by this author on: Oxford Academic Jared A Lashway Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine Search for other works by this author on: Oxford Academic Emma E Brown Renal-Electrolyte Division Search for other works by this author on: Oxford Academic Corry B Bondi Renal-Electrolyte Division Search for other works by this author on: Oxford Academic
, Cary R Boyd-Shiwarski Renal-Electrolyte Division Search for other works by this author on: Oxford Academic Roderick J Tan Renal-Electrolyte Division Search for other works by this author on: Oxford Academic Michael J Jurczak Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine Search for other works by this author on: Oxford Academic Ora A Weisz Renal-Electrolyte Division Corresponding author: Ora A. Weisz. Renal-Electrolyte Division, University of Pittsburgh School of Medicine, 3550 Terrace St. Pittsburgh, PA 15261. E-mail: weisz@pitt.edu Search for other works by this author on: Oxford Academic
Function, zqae026, https://doi.org/10.1093/function/zqae026
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20 May 2024
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Elynna B Youm, Katherine E Shipman, Wafaa N Albalawy, Amber M Vandevender, Ian J Sipula, Youssef Rbaibi, Allison E Marciszyn, Jared A Lashway, Emma E Brown, Corry B Bondi, Cary R Boyd-Shiwarski, Roderick J Tan, Michael J Jurczak, Ora A Weisz, Megalin knockout reduces SGLT2 expression and sensitizes to Western diet-induced kidney injury, Function, 2024;, zqae026, https://doi.org/10.1093/function/zqae026
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Abstract
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. Studies in our lab have shown that knock out (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD.
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© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.
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ORIGINAL RESEARCH
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