Kidney Proximal Tubule GLUT2—More than Meets the Eye

Abstract

Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.

Comprehensive strategy for identifying extracellular vesicle surface proteins as biomarkers for chronic kidney disease

“…Solute carrier family 2 member 2 (GLUT2) is a facilitative hexose transporter that mediates the transport of glucose, fructose, and galactose. Recently, GLUT2 has emerged as a central regulator in the pathogenesis of diabetic kidney disease ( Ahmad et al, 2022 ).…”

Physiological functions of glucose transporter-2: From cell physiology to links with diabetes mellitus

“…In human hepatocytes, GLUT-2 is a glucose-sensitive gene along with genes encoding type 1 pyruvate kinase and S14 fatty acid synthase [ 5 ]. In these cells, glucose-induced transcription is achieved by activating carbohydrate response element binding protein (ChREBP) transcription factor [ 9 ].…”

“…Interestingly, the group that discovered this mechanism also found that the GLUT-2 promoter lacks the carbohydrate response element ChoRE and instead contains the sterol response element SRE, which also binds sterol regulatory element-binding protein 1 (SREBP-1C) [ 10 , [17] , [18] , [19] ]. This transcription factor controls the transcription of lipogenic genes that require simultaneous regulation of insulin and blood glucose concentrations, and in the pancreas, it regulates GLUT-2 transcription more strongly than ChREBP [ 5 , 18 ]. Therefore, GLUT-2 expression is regulated by blood glucose concentration and adipogenesis factors, although additional regulatory factors beyond the above may be involved, waiting for discovery.…”

“…Solute carrier family 2 (GLUT-2) has captured the attention of many scholars due to its tissue specificity and the complexity of gene expression regulation [ 5 , 6 ]. Its expression is in the intestine and liver of streptozotocin-induced laboratory mice with hypoinsulinemia and hyperglycemia, suggesting that both conditions enhance GLUT-2 expression.…”

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

“…47,52,55 The proximal tubule emerges as a major source (rather than a consumer) of glucose; it supports blood glucose through gluconeogenesis in the fasting state and by SGLT2mediated tubular reabsorption in the postprandial state. 56,57 These shifts are achieved by SIRT1 (which is upregulated as proximal tubular glucose declines), 58 by activation of AMPK (which increases fatty acid oxidation, ATP production, and Na 1 /K 1 -ATPase activity), [59][60][61] and by downregulation of HIF-1a. 38,62 Hence, the perinatal changes in metabolism and in nutrient signaling in the proximal renal tubule represent a shift from a fetal nutrient surplus to an adult nutrient deprivation state.…”