TY - JOUR
T1 - Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis
AU - Hughes, Corey B.
AU - Mussman, George M.
AU - Ray, Phil
AU - Bunn, Robert C.
AU - Cornea, Virgilius
AU - Thrailkill, Kathryn M.
AU - Fowlkes, John L.
AU - Popescu, Iuliana
N1 - Publisher Copyright:
© 2021, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - Gluconeogenesis
KW - Kidney
KW - Mutation
KW - Phenotype
KW - SGLT2
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U2 - 10.1007/s00441-020-03358-8
DO - 10.1007/s00441-020-03358-8
M3 - Article
C2 - 33409652
AN - SCOPUS:85099251617
SN - 0302-766X
VL - 384
SP - 527
EP - 543
JO - Cell and Tissue Research
JF - Cell and Tissue Research
IS - 2
ER -