ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO127

Autophagy Activates EGR1 via ERK to Induce FGF2 in Renal Tubular Cells for Fibroblast Activation and Fibrosis During Maladaptive Kidney Repair

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    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
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background

Autophagy contributes to the regulation of maladaptive kidney repair including the development of tubulo-interstitial fibrosis. Our recent work reveals an autophagy-dependent tubular production and secretion of FGF2 into the interstitium where it acts as a key paracrine factor to activate fibroblasts for renal fibrosis. The mechanism by which autophagy induces FGF2 in renal tubular cells to promote maladaptive repair after AKI remains unclear.

Methods

Using various genetic and pharmacological approaches, this study examined the transcription factor early growth response protein 1 (EGR1) in post-ischemic mouse kidney tissues and in TGF-β1-treated proximal tubular cells.

Results

Following ischemic AKI, EGR1 was induced in the nuclei of chronically injured proximal tubules that were KIM-1-positive. Compared with wild-type mice, autophagy deficiency in iRT-Atg7 KO (inducible, renal tubule-specific Atg7 knockout) mice suppressed EGR1 expression in kidneys, indicating the induction of EGR1 was mediated by tubular cell autophagy. Consistently, TGF-β1 treatment induced EGR1 in cultured proximal tubular cells, which was also attenuated in Atg7 KO tubular cells and by autophagy inhibitors. In TGF-β1-treated cells, EGR1 knockdown inhibited FGF2 mRNA and protein expressions. ChIP assay further detected an increased binding of EGR1 to Fgf2 gene promoter region for transcriptional activation during TGF-β1 treatment. Interestingly, both FGF2 and EGR1 induction at mRNA levels were inhibited by FGF2 neutralizing antibody, suggesting a positive feedback between FGF2 and EGR1 that may contribute to EGR1-mediated FGF2 autoregulation. This feedback mechanism was further confirmed in Fgf2 KO primary tubular cells and Fgf2 KO mice. Upstream of EGR1, MAPKs (ERK, P38 and JNK) were activated in both post-ischemic kidneys and TGF-β1-treated tubular cells, whereas only ERK activation was attenuated by autophagy inhibition. Moreover, inhibition of ERK suppressed EGR1 induction in TGF-β1-treated tubular cells.

Conclusion

Together, these results suggest that autophagy activates ERK in tubular cells, which induces EGR1 for FGF2 transcription and autoregulation. FGF2 is then secreted into the interstitium for the activation of fibroblasts for fibrogenesis.

Funding

  • NIDDK Support