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Kidney Week

Abstract: TH-PO887

Impact of Angiotensin Receptor Blockade on Metabolic Profiles in a Mouse Model of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Azushima, Kengo, Duke-NUS Medical School, Singapore, Singapore
  • Kovalik, Jean-Paul, Duke-NUS Medical School, Singapore, Singapore
  • Ching, Jianhong, Duke-NUS Medical School, Singapore, Singapore
  • Gurley, Susan B., Oregon Health and Science University, Portland, Oregon, United States
  • Coffman, Thomas M., Duke-NUS Medical School, Singapore, Singapore
Background

Changes in energy metabolism have been associated with susceptibility to diabetic nephropathy (DN). Blockade of the renin-angiotensin system (RAS) is renoprotective in DN, but effects of RAS inhibition on metabolic profiles in DN have not been clearly defined. To investigate this issue, we carried out metabolomics profiling in a mouse model of DN and tested the effects of RAS blockade on kidney metabolism.

Methods

We generated a mouse model of DN with underlying activation of the RAS by a renin transgene (ReninTg) driven by the albumin promoter on the Akita background of type I diabetes. We have shown that on a 129 strain background, Akita-ReninTg mice exhibit cardinal characteristics of human DN including high-grade albuminuria and glomerulosclerosis. 12-week old 129 Akita-ReninTg mice were treated with vehicle or the angiotensin receptor blocker (ARB) losartan for 12 weeks. Following treatment, kidneys were collected and metabolic profiles were determined by liquid chromatography-mass spectrometry.

Results

Before treatment, the 129 Akita-ReninTg mice had significant albuminuria (833±112 µg/day). Over the next 12 weeks, there was a progressive increase of albuminuria in the vehicle group that was prevented by ARB (1480±562 vs 193±42 µg/day; p=0.045). When compared to age-matched 129/SvEv parental controls, metabolomics profiles of kidneys from vehicle-treated 129 Akita-ReninTg mice showed significant reductions in levels of most amino acids, except for the branched-chain amino acids, while C3 and C5 acyl-carnitine levels were increased. ARB had no effect on these profiles. By contrast, most even-chain acyl-carnitine levels were substantially reduced in 129 Akita-ReninTg mice compared to parental controls and C2 acyl-carnitine level was increased toward normal with ARB.

Conclusion

There is a range of metabolic alterations in this DN model, suggesting multiple disruptions of metabolic pathways in the kidney. Reduced levels of even-chain acyl-carnitines in mice with DN suggest altered renal fuel metabolism and may reflect impaired fatty acid oxidation. The impact of RAS blockade on renal metabolic profiles was discrete, confined to a partial restoration of kidney C2 acyl-carnitine level, reflecting normalisation of renal fuel metabolism. These metabolic actions may contribute to the renoprotective effects of ARB.

Funding

  • Government Support - Non-U.S.