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Abstract: TH-OR08

Differential Roles of Regnase3 in Resident Macrophages vs. Renal Tubular Epithelial Cells in Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Chenyu, Klinikum der Universitat Munchen Medizinische Klinik und Poliklinik IV - Standort Ziemssenstrasse, Munchen, Bayern, Germany
  • Anders, Hans J., Klinikum der Universitat Munchen Medizinische Klinik und Poliklinik IV - Standort Ziemssenstrasse, Munchen, Bayern, Germany
Background

RNA-binding proteins are a class of proteins that regulate RNA and have been implicated in a wide range of diseases. Regnase3 as one of those proteins has been shown to promote inflammation by increasing TNF in macrophages (Mφ). However, the full extent of its functions in kidney disease remains unknown. We hypothesized that Regnase3 plays a role in both kidney resident Mφ and renal tubular epithelial cells (RTEC), influencing inflammation and kidney repair after injury.

Methods

A series of genetically-modified mice were developed, including the Pax8rTtA, TetOCre, receptor activator of nuclear factor kappa-Β (Rank, a lineage tracer for kidney resident Mφ)-Cre (RankCre), and Regnase3 floxed (Regnase3fl/fl) mice. Upon these mice, we applied a range of kidney injury models involving unilateral ischemia-reperfusion and nephrocalcinosis. Furthermore, scRNA-seq and RNA-seq were utilized to investigate the underlying mechanisms.

Results

The scRNA-seq showed both Regnase3 is highly expressed in the kidney Mφ and positively correlated with the chemokines, Mφ phagocytosis, and Mφ maturation after kidney injury. In vivo, after the kidney injury, the RankCre-Regnase3fl/fl (Regnase3 conditional KO in kidney resident Mφ) mice suffered from more inflammation, characterized by CCR2 positive pro-inflammatory Mφ accumulation. In vitro, Regnase3 is involved in modulating resident Mφ polarization towards the pro-inflammatory and migration, indicating that it contributes to Mφ-related inflammation.

Next, we aimed to examine the role of Regnase3 in RTEC. Through in silico, we found that Regnase3 is highly expressed in healthy RTEC but reduced following injury, and it controls early apoptosis. In vivo and in vitro experiments suggested that the Regnase3 deletion in RTEC (Pax8rTtA-TetOCre-Regnase3fl/fl) against kidney injury and promote the repair of RTEC. Regnase3 targets pre-RNA and modulates alternative splicing by increasing skipped exon events and decreasing the probability of retained intron events.

Conclusion

Regnase3 contributes to kidney injury but the impact of it is contingent upon the specific cell lineage in question. The RankCre-Regnase3fl/fl leads to an exacerbation of kidney injury by increasing pro-inflammatory Mφ recruitment, whereas the Pax8rTtA-TetOCre-Regnase3fl/fl leads to an improvement after injury through its effects on cell death and RTEC repair.