Kidney Week

Abstract: SA-PO845

AMPK Deficiency Worsens Albuminuria Post Uninephrectomy (UNX)

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Rivera, Daniel, Keck School of Medicine of USC, Los Angeles, California, United States

Daniel Rivera,

• Rajani, Roshan, Keck School of Medicine of USC, Los Angeles, California, United States

Roshan Rajani,

• Mancino, Valeria, University of Southern California, Los Angeles, California, United States

Valeria Mancino,

• Rezapoor, Parisa, Keck School of Medicine of USC, Los Angeles, California, United States

Parisa Rezapoor,

• Zohoorkari, Hamidreza, Keck School of Medicine of USC, Los Angeles, California, United States

Hamidreza Zohoorkari,

• Saitta, Biagio, Keck School of Medicine of USC, Los Angeles, California, United States

Biagio Saitta,

• Ho, Pei-Yin, Keck School of Medicine of USC, Los Angeles, California, United States

Pei-Yin Ho,

• Li, Hui, Keck School of Medicine of USC, Los Angeles, California, United States

Hui Li,

• Hallows, Kenneth R., Keck School of Medicine of USC, Los Angeles, California, United States

Kenneth R. Hallows,

• Pastor-Soler, Nuria M., Keck School of Medicine of USC, Los Angeles, California, United States

Nuria M. Pastor-Soler,

Background

Living donor (LD) kidney transplant offers the best prognosis for end-stage kidney disease patients. LDs have excellent outcomes, yet recent studies show that in the first year post-UNX there is an increased risk of hypertension that also drives microalbuminuria, a marker of kidney injury. Although hypertrophy contributes to a new steady-state in kidney function, it is unclear whether compensatory changes are beneficial long term for the LD. In several chronic kidney disease (CKD) models activity of the metabolic sensor AMP-activated kinase (AMPK) decreases compared to healthy kidneys. We hypothesize that low AMPK activity pre-UNX could worsen CKD post-UNX when combined with a high-Na+ diet. Our work aims to inform mechanisms that could lead to protective interventions for LDs with approved AMPK activators.

Methods

We used adult female mice with double-floxed AMPK alpha subunits (AMPKfl) and ± tamoxifen-driven(Tam) expression of CAG-Cre recombinase (Cre+ vs. Cre-AMPKfl). All mice underwent UNX 5 wks post-Tam and were placed on a high-Na+ (HNa) diet at that time (intervention). We measured GFR, urine albumin and plasma electrolytes at different time points. Explanted Kidneys (EK) were examined by immunoblot and qPCR.

Results

EK from Cre+AMPKfl have significant (>75%) AMPK knockdown (KD) compared to Cre-AMPKfl mice after Tam. No changes in kidney injury marker-1 gene expression were found in EK between the two groups. However, AMPK-KD (Cre+ mice) had a significant increase in albuminuria (overnight: 22.1±4 vs. 9.2±2 mg, Cre+ vs. Cre-, P<0.03) and anemia. UNX+HNa significantly increased albuminuria in Cre-AMPK (9.2 pre vs. 27.7 post, P<0.02), while in the AMPK-KD group this difference was more pronounced (22.1 pre vs 65.5 post, P<0.01). At two weeks after UNX+HNa there was a statistically significant increase in GFR and metabolic acidosis in both groups compared to pre-intervention. However, at that time there was no difference in GFR between Cre+ and Cre-AMPK mice.

Conclusion

Although female rodents have less severe kidney injury post-UNX than males, our studies show that AMPK KD in female mice worsens kidney injury (albuminuria) in a model of kidney donation and HNa diet. These findings implicate AMPK as an important target for potential pharmacologic interventions to prevent CKD in LDs.

Funding

• NIDDK Support