Augmenter of liver regeneration inhibits renal fibrosis during acute kidney injury to chronic kidney disease transition by regulating autophagic flux

Background

Augmenter of liver regeneration (ALR) is believed to protect against acute kidney injury (AKI). The objective of this study was to investigate the mechanisms of ALR in the transition from AKI to chronic kidney disease (CKD).

Methods

ALR Conditional Knockout (CKO) mice were bilateral renal artery clamped to induce AKI and CKD. Serum creatinine, blood urea nitrogen, and uric acid were measured to reflect renal function. Renal histology was used to assess kidney damage. Transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to identify differentially expressed genes (DEGs) and related pathways. TUNEL assay was conducted to assess apoptosis. Polymerase chain reaction and immunohistology were used to analyze autophagy-related factors and kidney fibrosis. AAV9-mRFP-GFP-LC3 was injected to observe autophagy flux.

Results

In the murine models of AKI and CKD, loss of ALR led to markedly reduced renal function and renal tubular pathology injury. Multiple autophagy-related pathways were found to be enriched in up-regulated DEGs in transcriptome sequencing of ALR CKO and control groups with AKI. Renal fibrosis was evident in ALR CKO mice, with marked suppression of Beclin-1, a factor associated with the initiation phase of autophagy, and ATG5, an important factor in the extension phase of autophagosomes. The marked accumulation of LC3 and SQSTM1/P62, which is associated with the formation of autophagosomes, was also observed, suggesting an impairment of autophagic processes. Correspondingly, the AAV9-mRFP-GFP-LC3 results indicated that decreased ALR led to the accumulation of autophagosomes and impaired autophagic lysosome generation.

Conclusions

Collectively, these results suggested that ALR deficiency led to apoptosis and enhanced renal fibrosis by impairing autophagic flux, which in turn led to the transition of AKI to CKD.