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Kidney Week

Abstract: PO0693

Hyperglycemia-Induced Mitochondrial Dysfunction in Kidney and Brain Are Protected by β-Hydroxybutyrate Treatment

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Drel, Viktor, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Holstein, Deborah, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Kim, Jiwan John, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Pamreddy, Annapurna, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Lechleiter, James Donald, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background

The immediate effects of hyperglycemia on mitochondrial and organ dysfunction are poorly understood. Acute hyperglycemia could reveal key initiating events to determine how organ dysfunction ensues, particularly in response to repeated hyperglycemia exposures as occurs with poorly controlled diabetes. The potential protective benefit of ketone bodies on mitochondrial function across organs during hypergylcemia has also not been well characterized. Here, we evaluated effects of hyperglycemia and β-hydroxybutyrate (BHB) on ATP production in the mouse using a novel in vivo brain imaging approach in combination with MALDI-MSI.

Methods

GFAP-fLuc dual-glo transgenic mice were used to test the effect of BHB on brain luciferin-luciferase biolumenescence using a Xenogen IVIS spectrum live-imaging system. Transgenic dual-glo mice expressed the luciferase in astrocytes under the gfap promoter. MALDI-MSI analysis was used to detect the acute impact of BHB on small molecule metabolites in the kidneys and brains of C57BL/6J mice. For in vivo experiments, mice were administered either 2.5 g/kg of BHB, 2 g/kg of glucose, a combination of BHB and glucose, or 0.9% NaCl (vehicle control). We determined the timing effect of 20 mM BHB on mitochondria function and glycolysis in HK2 cells, in fresh mice kidney, and in brain tissue using pH and OCR measurements with the Agilent Seahorse instrument.

Results

We found reduced levels of ATP in both brain and kidney tissue slices of mice acutely treated with 25 mM glucose with MALDI-MSI. BHB treatments increased ATP levels in the brain and kidney tissues and cells. Acute glucose exposure in HK2 cells reduced OCR and increased ECAR, which was blocked by BHB treatment. In vivo, brain bioluminescence was significantly decreased when mice were injected with 25 mM glucose (4 minutes after luciferin injections), consistent with a loss in ATP production. In contrast BHB injections increased biolumenscence and blocked the loss of signal in the presence of high glucose.

Conclusion

These data indicate that acute glucose exposure reduces ATP production in the kidney and brain, and that BHB can reverse this effect. Together, these studies suggest the acute detrimental effects of hyperglycemia on metabolism and mitochondrial dysfunction can be reversed with ketone bodies treatment.

Funding

  • Private Foundation Support