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Abstract: FR-PO960

The Neuropeptide SP/NK-1R Axis Promotes Renal Interstitial Fibrosis via MAPK Pathway in Unilateral Ureteral Obstruction Mice

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Zhu, Enyi, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, China
  • Zhong, Ming, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, China
  • Liu, Yang, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, China
  • Liu, Yu, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, China
  • Li, Jinhong, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, China
  • Zheng, Zhihua, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, China
Background

Renal interstitial fibrosis is considered to be the major contributor to chronic progressive kidney function loss, and suggested as a significant predictor of renal survival in chronic kidney disease. The potential mechanism which initiates the profibrogenic process during kidney injury is not completely understood. Substance P (SP) is a proinflammatory neuropeptide that binds to its high-affinity receptor neurokinin1-receptor (NK-1R) and it has been involved in multiple fibrotic diseases. However, the role of SP/NK-1R axis in renal interstitial fibrosis is largely undefined.

Methods

To investigate the role of SP/NK-1R in renal interstitial fibrosis, mice were administrated with NK-1R pharmacological inhibitor or SP during unilateral ureteral obstruction (UUO) and NK-1R−/− mice were subjected to UUO. Cell counting, colony formation, apoptosis, cell cycle and RNA-seq analysis were performed in tubular epithelium cells to explore the mechanism of SP/NK-1R.

Results

SP and NK-1R were overexpressed in renal tubular epithelial cells of mice after UUO. In addition, pharmacological and genetic inhibition of NK-1R resulted in reduction of interstitial inflammation, fibrosis and renal cell apoptosis, whereas SP treatment aggravated UUO-induced progressive damage. In vitro, SP administration suppressed growth of NK-1R-overexpressed HK-2 cells, and promoted apoptosis, G2/M arrest and expression of profibrogenic genes, which could be dramatically rescued by NK-1R inhibitor. Mechanistically, RNA-seq analysis revealed that differential expressed genes between NK-1R-ovexpressed HK-2 cells with and without SP treatment were mainly enriched in MAPK signaling. Consistently, phosphorylated p38/JNK levels were increased in SP-treated cells and mice obstructed kidneys. Furthermore, inhibition of NK-1R decreased expression of phosphorylated p38/JNK in SP-treated cells and mice subjected to UUO. In support, the p38 or JNK specific inhibitors partly alleviated SP-mediated effect, and intriguingly, combined use of p38/JNK inhibitors further ameliorated it.

Conclusion

These results demonstrate that neuropeptide SP/NK-1R axis plays an important role in kidney interstitial fibrosis via activating the MAPK pathway of renal tubular epithelial cells, which may be a promising therapeutic target for chronic kidney disease.