title: SGLT2 Inhibitors: Glucotoxicity and Tumorigenesis Downstream the Renal Proximal Tubule?
abstract: At present, diabetes mellitus is the main cause of end-stage renal disease. Effective glycaemic management is the most powerful tool to delay the establishment of diabetic complications, such as diabetic kidney disease. Together with reducing blood glucose levels, new anti-diabetic agents are expected not only to control the progression but also to restore known defects of the diabetic kidney. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising anti-diabetic agents that reduce hyperglycaemia by impairing glucose reabsorption in proximal tubule of the kidney and increasing glucosuria. SGLT2 inhibitors have shown to reduce glucotoxicity in isolated proximal tubule cells and also to attenuate expression of markers of overall kidney damage in experimental animal models of diabetes, but the actual renoprotective effect for downstream nephron segments is still unknown and deserves further attention. Here, we briefly discuss possible undesired effects of enhanced glucosuria and albuminuria in nephron segments beyond the proximal tubule after SGLT2 inhibitor treatment, offering new lines of research to further understand the renoprotective action of these anti-diabetic agents. Strategies blocking glucose reabsorption by renal proximal tubule epithelial cells (RPTEC) may be protective for RPTEC, but downstream nephron segments will still be exposed to high glucose and albumin levels through the luminal face. The actual effect of constant enhanced glucosuria over distal nephron segments remains to be established. J. Cell. Physiol. 231: 1635-1637, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile.
authors.forename: Romina
authors.initials: R
authors.lastname: Bertinat
authors.affiliation: Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Nualart
authors.affiliation: Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile.|Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Yáñez
mesh_terms: D000419:Albuminuria / Q000139:chemically induced*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D003920:Diabetes Mellitus / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006029:Glycosuria / Q000139:chemically induced*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000139:chemically induced*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D018570:Risk Assessment; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors