Abstract: TH-PO1027

Metabolic Acidosis Inhibits AMPK Function in Kidney Cells

Session Information

  • Acid Base: Basic
    November 02, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 701 Acid-Base: Basic

Authors

  • Pastor-Soler, Nuria M., Keck School of Medicine of USC, Los Angeles, California, United States
  • Li, Hui, Keck School of Medicine of USC, Los Angeles, California, United States
  • Omi, Kazuhiro, University of Southern California, Los Angeles, California, United States
  • Hallows, Kenneth R., Keck School of Medicine of USC, Los Angeles, California, United States
Background

AMP-activated protein kinase (AMPK) is stimulated by cellular metabolic depletion. We have shown that AMPK activation inhibits kidney membrane transport proteins, thus protecting cells from further metabolic depletion and damage. AMPK is tightly regulated, and when pharmacologically activated, can protect kidneys from superimposed injury. Conversely, AMPK is inhibited in chronic kidney disease (CKD) and pharmacologic AMPK activators are proposed as therapies to slow CKD progression. However, the mechanisms by which AMPK may promote kidney survival are unclear. CKD results in systemic metabolic acidosis (MA) due to the inability of the kidney to excrete non-volatile acid. MA often goes undetected and, if untreated, MA has severe health sequelae such as worsening glomerular filtration rate (GFR). We hypothesized is that there is cross-talk between acid-base status and AMPK signaling, and that dysregulation of AMPK function by MA disrupts kidney regeneration.

Methods

We used kidney epithelial cell lines in culture and adult male C57BL/6 mice for our experiments. Cells were exposed to media at either pH 7.3-7.4 (control) or 6.9-7.0 (acidic) for 3 d ± an AMPK activator for the last 16 h. Mice were given 1.5% saccharin ± 0.28 M NH4Cl in the drinking water for 2 months. Mice also underwent uninephrectomy (UNX) as a model for CKD vs. sham surgery. To evaluate the AMPK pathway in tissue, we examined levels of phosphorylation of acetyl CoA carboxylase (pACC) by immunoblot.

Results

We found that as compared to cells grown at pH 7.4, kidney cells grown in acidic media have reduced baseline AMPK activity and blunted pharmacologic AMPK activation. Mice on the acidogenic diet developed MA without significant weight loss compared to mice on the control diet (blood pH 7.2 vs 7.3 ± 0.01). In mice after UNX, the superimposed MA induced a statistically significant decrease in pACC, compared to mice with UNX in a control diet.

Conclusion

Our results point to a direct inhibition of the AMPK pathway in the setting of combined CKD and MA. This AMPK inhibition may be detrimental to kidney regeneration in the setting of CKD and MA.

Funding

  • NIDDK Support