Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease
Abstract Metformin (MET) has the potential to activate p‐AMPK and block mTORC1‐induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Physiological Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.14814/phy2.15776 |
| _version_ | 1827389717742616576 |
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| author | Ozgur A. Oto Daniel J. Atwood Anjana Chaudhary Zhibin He Amy S. Li Michael F. Wempe Charles L. Edelstein |
| author_facet | Ozgur A. Oto Daniel J. Atwood Anjana Chaudhary Zhibin He Amy S. Li Michael F. Wempe Charles L. Edelstein |
| author_sort | Ozgur A. Oto |
| collection | DOAJ |
| description | Abstract Metformin (MET) has the potential to activate p‐AMPK and block mTORC1‐induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate. MET 150 mg/kg resulted in a therapeutic serum metformin level but had no effect on kidney weight, cyst indices, kidney function, or mTOR and autophagy proteins. In summary, a standard dose of MET was ineffective in reducing PKD, did not activate p‐AMPK or suppress mTOR and the higher dose resulted in increased lactate levels and nephrotoxicity. In conclusion, the study dampens enthusiasm for human studies of MET in PKD. Doubling the metformin dose resulted in a 10‐fold increase in mean blood levels and toxicity suggesting that the dosage range between therapeutic and toxic is narrow. |
| first_indexed | 2024-03-08T16:41:54Z |
| format | Article |
| id | doaj.art-37f78461b061403ab45d555a577cbf8f |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-08T16:41:54Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-37f78461b061403ab45d555a577cbf8f2024-01-05T09:46:30ZengWileyPhysiological Reports2051-817X2023-09-011117n/an/a10.14814/phy2.15776Metformin does not slow cyst growth in the PCK rat model of polycystic kidney diseaseOzgur A. Oto0Daniel J. Atwood1Anjana Chaudhary2Zhibin He3Amy S. Li4Michael F. Wempe5Charles L. Edelstein6Division of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora Colorado USADivision of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora Colorado USADivision of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora Colorado USADivision of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora Colorado USADivision of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora Colorado USADepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora Colorado USADivision of Renal Diseases and Hypertension University of Colorado Anschutz Medical Campus Aurora Colorado USAAbstract Metformin (MET) has the potential to activate p‐AMPK and block mTORC1‐induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate. MET 150 mg/kg resulted in a therapeutic serum metformin level but had no effect on kidney weight, cyst indices, kidney function, or mTOR and autophagy proteins. In summary, a standard dose of MET was ineffective in reducing PKD, did not activate p‐AMPK or suppress mTOR and the higher dose resulted in increased lactate levels and nephrotoxicity. In conclusion, the study dampens enthusiasm for human studies of MET in PKD. Doubling the metformin dose resulted in a 10‐fold increase in mean blood levels and toxicity suggesting that the dosage range between therapeutic and toxic is narrow.https://doi.org/10.14814/phy2.15776metforminpolycystic kidney |
| spellingShingle | Ozgur A. Oto Daniel J. Atwood Anjana Chaudhary Zhibin He Amy S. Li Michael F. Wempe Charles L. Edelstein Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease Physiological Reports metformin polycystic kidney |
| title | Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease |
| title_full | Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease |
| title_fullStr | Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease |
| title_full_unstemmed | Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease |
| title_short | Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease |
| title_sort | metformin does not slow cyst growth in the pck rat model of polycystic kidney disease |
| topic | metformin polycystic kidney |
| url | https://doi.org/10.14814/phy2.15776 |
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