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Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis

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Abstract

Inhibitors of sodium/glucose co-transporter 2 (SGLT2) are currently in clinical use for type 2 diabetes (T2D) treatment due to their anti-hyperglycemic effect exerted by the inhibition of glucose reabsorption in the kidney. Inhibition of SGLT2 is associated with improvement of renal outcomes in chronic kidney disease associated with T2D. Our study aimed to describe the renal-specific phenotypic consequences of the SGLT2-loss of function “Jimbee” mutation within the Slc5a2 mouse gene in a non-diabetic/non-obese background. The Jimbee mice displayed reduced body weight, glucosuria, polyuria, polydipsia, and hyperphagia but were normoglycemic, with no signs of baseline insulin resistance or renal dysfunction. Histomorphological analysis of the kidneys revealed a normal architecture and morphology of the renal cortex, but shrinkage of the glomerular and tubular apparatus, including Bowman’s space, glomerular tuft, mesangial matrix fraction, and proximal convoluted tubule (PCT). Immunofluorescent analysis of renal sections showed that SGLT2 was absent from the apical membrane of PCT of the Jimbee mice but remnant positive vesicles were detected within the cytosol or at the perinuclear interface. Renal localization and abundance of GLUT1, GLUT2, and SGLT1 were unchanged in the Jimbee genotype. Intriguingly, the mutation did not induce hepatic gluconeogenic gene expression in overnight fasted mice despite a high glucose excretion rate. The Jimbee phenotype is remarkably similar to humans with SLC5A2 mutations and provides a useful model for the study of SGLT2-loss of function effects on renal architecture and physiology, as well as for identifying possible novel roles for the kidneys in glucose homeostasis and metabolic reprogramming.

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Acknowledgments

We thank Dr. Thomas Wilkop, from the Light Microscopy Core at the University of Kentucky, Lexington, KY, for imaging services and valuable advice regarding the SIM experiments. This research was supported by the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). The mouse strain used for this research project, C57BL/6J-Slc5a2m1Btlr/Mmmh, RRID: MMRRC_036517-MU, (the “Jimbee” strain) was obtained from the Mutant Mouse Resource and Research Center (MMRRC) at University of Missouri, an NIH-funded strain repository, and was donated to the MMRRC by Bruce Beutler, M.D., University of Texas Southwestern Medical Center.

Funding

This work was supported by grants from the National Institutes of Health, R21AR070620 (to K.M.T.) and R56DK084045 (to J.L.F.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Research Endowment. C.B.H and G.M.M were students enrolled in the HON385/ BIO395, respectively BIO395 Mentored Research Programs of the University of Kentucky under the mentorship of I.P.

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  1. Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, 900 S. Limestone, CTW469, Lexington, KY, 40536, USA

    Corey B. Hughes, George M. Mussman, Phil Ray, Robert C. Bunn, Kathryn M. Thrailkill, John L. Fowlkes & Iuliana Popescu

  2. Department of Pediatric Endocrinology, University of Kentucky College of Medicine, 2195 Harrodsburg Rd, Lexington, KY, 40504, USA

    Phil Ray, Robert C. Bunn, Kathryn M. Thrailkill & John L. Fowlkes

  3. Department of Pathology, University of Kentucky Medical Center, 800 Rose Street, MS117, Lexington, KY, 40536, USA

    Virgilius Cornea

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Experiments on animals were approved by the local Institutional Animal Care and Use Committee (IACUC# 2015-2293) of the University of Kentucky, Lexington KY. All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Hughes, C.B., Mussman, G.M., Ray, P. et al. Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis. Cell Tissue Res 384, 527–543 (2021). https://doi.org/10.1007/s00441-020-03358-8

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