Kidney Week

Abstract: TH-PO101

Dysregulated Tubular Autophagy Promotes Maladaptive Kidney Repair and Interstitial Fibrosis During AKI-CKD Transition

Session Information

• AKI: Inflammation, New Technologies, Omics
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Livingston, Man J., Augusta University Medical College of Georgia, Augusta, Georgia, United States

Man J. Livingston,

• Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States

Zheng Dong,

Background

Tubular cell injury is a key pathological feature of AKI. Renal tubules have the capacity to regenerate after injury, but kidney repair following severe AKI is often incomplete, leading to interstitial fibrosis and CKD. The mechanisms underlying AKI-CKD transition are poorly understood. Autophagy is induced in tubular cells during AKI and protects against injury. Recent work further reveals a profibrotic role of tubular autophagy in UUO. However, the role of autophagy in kidney repair and fibrosis after AKI remains unknown.

Methods

We established an inducible, conditional knockout mouse model where Atg7 can be ablated specifically from renal tubules at a desired time. Using this model we examined the role of tubular autophagy in the development of chronic renal pathologies after ischemic AKI.

Results

Mice underwent 30-min unilateral renal ischemia followed by reperfusion for up to 4 wks. Autophagy was persistently activated in proximal tubules of post-ischemic kidneys, as indicated by LC3-II accumulation and increased formation of both autophagosomes and autolysosomes. We generated a doxycycline-inducible, renal tubule-specific Atg7 knockout mouse model (iAtg7 KO) where Atg7 was specifically deleted from renal tubules only during the recovery phase after AKI without affecting initial injury. The inducible Atg7 KO blocked autophagy in renal tubules and also suppressed post-ischemic fibrosis. Proliferation and activation of fibroblasts was inhibited in iAtg7 KO mice, so was the accumulation of ECM components. Wild-type (WT) mice had 10.1% interstitial fibrosis 2-wk after AKI and 17.5% at 4-wk, which were reduced to 6.7% at 2-wk and 9.9% at 4-wk respectively in iAtg7 KO mice. AKI in WT mice led to decreased staining of brush border marker LTL and increased expression of vimentin in renal tubules indicating tubular degeneration, which were reversed in iAtg7 KO mice. Renal tubules in WT mice displayed remarkable senescent changes after ischemic AKI, which were significantly attenuated by autophagy deficiency. Under these conditions, G₂/M cell cycle arrest was also induced in renal tubules of WT but suppressed in iAtg7 KO kidneys.

Conclusion

These results suggest that autophagy in renal tubules may contribute to maladaptive kidney repair during AKI-CKD transition by promoting interstitial fibrosis via tubular atrophy, senescence, and cell cycle arrest.

Funding

• NIDDK Support