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Abstract: FR-PO120

AMPK Activation Improves Tissue Oxygenation in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Liu, Zhi Zhao, University of California, San Diego, San Diego, California, United States
  • Singh, Prabhleen, UC San Diego & VA San Diego Healthcare System, San Diego, California, United States
Background

Progressive intra-renal hypoxia is implicated in the pathogenesis of CKD. However, effective therapies to target intra-renal hypoxia are very limited. We have previously reported early alterations in renal oxygenation and oxygen demand-supply mismatch leading to hypoxia in subtotal nephrectomy (STN), a well-established experimental model of CKD. AMP-activated protein kinase (AMPK) is an important cellular metabolic sensor and regulator, which is dimished in CKD. In this study, we evaluated the quantitative changes in renal tissue oxygenation and the impact of AMPK activation by metformin (MET) on hypoxic and metabolic stress adaptation in STN.

Methods

Male Wistar rats were randomly divided into four groups/two time points: sham, sham+MET (250 mg/kg/day oral gavage), STN, STN+MET, and 1-week or 4-week treatment. Rats were anesthetized and placed on a temperature-controlled table. Left jugular vein, left femoral artery, and urinary bladder were cannulated. Intrarenal oxygen tension (pO2) was measured in the renal cortex and medulla by a Clark-type microelectrode (Unisense) after 60-min equilibration period.

Results

At 1-week post-STN, renal cortical pO2 declined in STN (33±10 vs. 52±7 mmHg in shams, p<0.0001). MET treatment improved the STN-induced decreased cortical pO2 (47±6 mmHg) (p<0.0001). At 4-week time point, renal cortical pO2 continued to be lower in STN (40±11 vs. 52±6 mmHg in shams, p=0.0008). MET prevented the STN-induced decrease in cortical pO2 (49±7 mmHg) (p=0.0031). However, in the renal medulla, the STN-induced decreased pO2 was not rescued by MET at both time points.

Conclusion

Our findings demonstrate that tissue oxygen tension is reduced in the STN kidneys in early and late stages. This was prevented by AMPK activation with metformin treatment in the renal cortex. Impact of AMPK activation on tubular transport and metabolism in STN is being investigated.

Funding

  • NIDDK Support