Abstract: FR-PO280
Metformin Worsens Kidney Function and Has No Effect on Cyst Growth in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease (ARPKD)
Session Information
- Genetic Diseases of the Kidneys: Cystic - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1101 Genetic Diseases of the Kidneys: Cystic
Authors
- Oto, Ozgur Akin, Istanbul Universitesi Istanbul Tip Fakultesi, Istanbul, Istanbul, Turkey
- Atwood, Daniel, University of Colorado Health, Aurora, Colorado, United States
- Chaudhary, Anjana, University of Colorado Health, Aurora, Colorado, United States
- Edelstein, Charles L., University of Colorado Health, Aurora, Colorado, United States
Background
Metformin (MET) has shown mixed results in reducing cyst growth in mouse models of PKD and in humans. Lactic acidosis has been suggested as a cause of the lack of efficacy of MET on cyst growth. The effect of MET on cyst growth in rat models of PKD is not known. The aim of this study was to determine the effects of MET on cyst growth, kidney function, mTOR signaling and lactate levels in a rat model of ARPKD
Methods
Male PCK rats, a Pkhd1 gene mutation model of human ARPKD were studied. PCK rats were treated with either vehicle (VEH) or metformin (300 mg/kg, IP) from 28-84 d of age. Autophagy and mTOR proteins were analyzed by quantitative immunoblot analysis (Relative densitometry units-RDU). BUN was measured with a urea assay kit (BioAssay Systems). Serum creatinine was measured by HPLC. Lactate levels were measured by an L-Lactate assay Kit (EnzymFluo). Cyst index was analyzed by a NIS Elements macro
Results
During the study 2 MET-treated rats died. Two kidney weight was not affected by MET (3.0 vs 3.1±0.4, p=0.6). Two kidney/body weight ratio (2K/BW) was high in MET group but there was significant weight loss. Cystic indexes were similar in both groups (3.7±1.9, 3.7±2.08, p=0.9). There was a significant increase in BUN and creatinine levels in MET group. MET is known to activate AMPK, suppress mTORC1 and induce autophagy. AMPK (pAMPK; 0.7 vs 1.3, ns), mTORC1 (pS6; 0.4 vs 0.8, ns) and mTORC2 (pAktS473) was not suppressed by MET (0.8 vs 0.5; ns) and conversion of LC3-I to LC3-II (a marker of autophagy) was not affected by MET (0.9 vs 1.6; ns). Lactate levels were significantly higher in MET group
Conclusion
A standard dose of MET did not slow cyst growth. MET increased lactate levels and was nephrotoxic (increased BUN and Creatinine). In conclusion, the study suggests that human studies of MET in PKD may be complicated by nephrotoxicity and that MET dosing should be carefully chosen in human PKD studies. Studies of a dose-response of MET on cyst growth, kidney function, lactate levels and mTOR/autophagy are underway in PCK rats
| Vehicle | Metformin | |
| BW (g) | 354.5±35.13 | 295.8±18.4* |
| 2K/BW (%) | 0.9±0.1 | 1.0±0.1* |
| BUN (mg/dl) | 23.8±4.1 | 31.0±3.6* |
| Creatinine (mg/dl) | 1.7±0.1 | 2.8±1.1* |
| Lactate level (uM) | 7479±1801 | 13168±4080* |
*P<0.05
Funding
- Veterans Affairs Support