Kidney Week

Abstract: TH-PO258

Loss of the Stress-Responsive Transcription Factor FoxO3 Accelerates AKI to CKD Transition

Session Information

• AKI Basic: Cell Death and Biomarkers
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

• 001 AKI: Basic

Authors

• Li, Ling, Columbia University College of Physicians & Surgeons, New York, New York, United States

Ling Li,

• Ha, Catherine, Columbia University College of Physicians & Surgeons, New York, New York, United States

Catherine Ha,

• Liu, Julia D, Columbia University College of Physicians & Surgeons, New York, New York, United States

Julia D Liu,

• Al-Awqati, Qais, Columbia University College of Physicians & Surgeons, New York, New York, United States

Qais Al-Awqati,

• Lin, Fangming, Columbia University College of Physicians & Surgeons, New York, New York, United States

Fangming Lin,

Background

AKI increases the risk for developing or worsening CKD. Capillary drop out and hypoxia occurs in kidneys transitioning from AKI to CKD. We recently found that hypoxia activated a stress-responsive transcription factor FoxO3 in mouse kidneys by the mechanism of preventing its oxygen-dependent degradation.

Methods

To test the function of FoxO3 activation during the AKI to CKD transition, we specifically deleted FoxO3 with high efficiency in tubular epithelial cells using Pax8-rtTA;Tet-O-cre;FoxO3^f/f mice.

Results

Ischemia-reperfusion injury (IRI) of a 35 min duration to the left kidney and right nephrectomy was performed. One week later, FoxO3 was deleted by giving mice doxycycline in the drinking water to study its role after the acute injury and recovery phase. Deletion of FoxO3 aggrevated renal damage 4 weeks post IRI indicated by significantly higher scores of brush border loss in proximal tubules, renal tubular atrophy and tubular cast formation (229 ± 5.3 vs. 22 ± 3.6 in wild type, n= 5). Furthermore, FoxO3 deleted mice had more prominent tubular cell apoptosis. However, neither interstitial fibrosis and inflammation nor microvascular density were significantly different compared with FoxO3 wild type mice. Mice with FoxO3 deletion also had higher urinary albumin:creatinine (53.2 ± 8.3 mg/g vs. 18.4 ± 4.6 mg/g in wild type, n=4) indicating that worse morphology was associated with functional decline. One potential mechanism for repair and survival of renal tubules is autophagy, a well-known cellular stress response. To examine the role of FoxO3 in renal autophagy, we examined the conversion of the core autophagy-related protein LC3I to LC3II, which is a key event in the formation of autophagic vesicles. Kidneys with FoxO3 deletion showed a 52% reduction in the ratio of LC3II to LC3I, suggesting lower level of autophagy.

Conclusion

In summary, our results indicate that FoxO3 activation induces renal autophagy as a stress response, which attenuates CKD development and progression.

Funding

• NIDDK Support