Phlorizin pretreatment reduces acute renal toxicity in a mouse model for diabetic nephropathy.
Streptozotocin (STZ) is widely used as diabetogenic agent in animal models for diabetic nephropathy (DN). However, it is also directly cytotoxic to kidneys, making it difficult to distinguish between DN-related and STZ-induced nephropathy. Therefore, an improved protocol to generate mice for DN studies, with a quick and robust achievement of the diabetic state, without direct kidney toxicity is required. To investigate the mechanism leading to STZ-induced nephropathy, kidney damage was induced with a high dose of STZ. This resulted in delayed gastric emptying, at least partially caused by impaired desacyl ghrelin clearance. STZ uptake in the kidneys is to a large extent mediated by the sodium/glucose cotransporters (Sglts) because the Sglt inhibitor phlorizin could reduce STZ uptake in the kidneys. Consequently, the direct toxic effects in the kidney and the gastric dilatation were resolved without interfering with the β-cell toxicity. Furthermore, pancreatic STZ uptake was increased, hereby decreasing the threshold for β-cell toxicity, allowing for single low non-nephrotoxic STZ doses (70 mg/kg). In conclusion, this study provides novel insights into the mechanism of STZ toxicity in kidneys and suggests a more efficient regime to induce DN with little or no toxic side effects.
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics.
Bas
B
Brouwers
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics.
Vincent P E G
VPEG
Pruniau
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics.
Elisa J G
EJG
Cauwelier
Gene Expression Unit, Department of Molecular Cell Biology, KU Leuven, 3000 Leuven.
Frans
F
Schuit
Department of Pathology, University Hospital Gasthuisberg, 3000 Leuven, Belgium.
Evelyne
E
Lerut
Department of Pathology, University Hospital Gasthuisberg, 3000 Leuven, Belgium.
Nadine
N
Ectors
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics. Electronic address: jeroen.declercq@med.kuleuven.be.
Jeroen
J
Declercq
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics.
John W M
JWM
Creemers
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D010695:Phlorhizin / Q000494:pharmacology*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013311:Streptozocin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D051269:Sodium-Glucose Transporter 1; D013311:Streptozocin; D010695:Phlorhizin
Diabetes; Diabetic Nephropathy; Gastric Dilatation; Glucose; Glucose Transport; Kidney; Mouse; Phlorizin; Sglt; Streptozotocin