Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis
| Autor: | Corey B. Hughes, George M. Mussman, Kathryn M. Thrailkill, Phil Ray, Virgilius Cornea, Robert C. Bunn, Iuliana Popescu, John L. Fowlkes |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Histology Renal cortex Kidney urologic and male genital diseases Pathology and Forensic Medicine Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Sodium-Glucose Transporter 2 Loss of Function Mutation Internal medicine medicine Animals Homeostasis Humans Glucose homeostasis biology business.industry Cell Biology medicine.disease Renal glucose reabsorption Glucose 030104 developmental biology medicine.anatomical_structure Endocrinology Diabetes Mellitus Type 2 biology.protein GLUT2 Female GLUT1 business 030217 neurology & neurosurgery Kidney disease |
| Zdroj: | Cell and Tissue Research. 384:527-543 |
| ISSN: | 1432-0878 0302-766X |
| DOI: | 10.1007/s00441-020-03358-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink