Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury.

Autor: Youm EB; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.; Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA., Shipman KE; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Albalawy WN; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.; Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA., Vandevender AM; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Sipula IJ; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Rbaibi Y; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Marciszyn AE; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Lashway JA; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Brown EE; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Bondi CB; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Boyd-Shiwarski CR; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Tan RJ; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Jurczak MJ; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Weisz OA; Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Jazyk: angličtina
Zdroj: Function (Oxford, England) [Function (Oxf)] 2024 Jul 11; Vol. 5 (4).
DOI: 10.1093/function/zqae026
Abstrakt: 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 knockout (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.
(© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)
Databáze: MEDLINE
Externí odkaz: