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Phlorizin pretreatment reduces acute renal toxicity in a mouse model for diabetic nephropathy
Bas Brouwers1, Vincent P E G Pruniau1, Elisa J G Cauwelier1
1Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics.
Abstract:
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.
Insights
This study reveals how streptozotocin (STZ) damages kidneys and proposes a new method to induce diabetic nephropathy (DN) in mice. The improved protocol minimizes kidney toxicity, enabling better diabetic nephropathy research.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Streptozotocin (STZ) is a common agent for inducing diabetes in animal models, but it also causes kidney toxicity.
- This direct nephrotoxicity complicates the study of diabetic nephropathy (DN) by confounding results.
- A refined method is needed to reliably induce diabetes without direct kidney damage.
Purpose of the Study:
- To investigate the mechanisms behind STZ-induced kidney damage.
- To develop an improved protocol for inducing diabetic states in mice with reduced nephrotoxicity.
- To enhance the reliability of animal models for diabetic nephropathy research.
Main Methods:
- Investigated STZ-induced nephropathy using high-dose STZ.
- Examined the role of sodium/glucose cotransporters (Sglts) in kidney STZ uptake using phlorizin.
- Assessed STZ effects on gastric emptying and pancreatic beta-cell function.
Main Results:
- High-dose STZ caused delayed gastric emptying, linked to impaired desacyl ghrelin clearance.
- Kidney STZ uptake is significantly mediated by Sglts; phlorizin reduced this uptake.
- Direct kidney toxicity and gastric issues were resolved by inhibiting Sglts, preserving beta-cell toxicity.
- Pancreatic STZ uptake increased, lowering the threshold for beta-cell toxicity and allowing single, low, non-nephrotoxic STZ doses (70 mg/kg).
Conclusions:
- Elucidated the mechanism of STZ nephrotoxicity, highlighting the role of Sglts.
- Developed a more efficient STZ administration protocol for inducing diabetic nephropathy in mice.
- The improved protocol minimizes toxic side effects, offering a more robust model for DN studies.
