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Kidney Week

Abstract: SA-PO104

The Fms-Like Tyrosine Kinase Receptor 3 Ligand/Dendritic Cell Axis Contributes to Kidney Recovery in AKI

Session Information

  • AKI: Mechanisms - III
    November 05, 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

  • Na, Li, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Guo, Yao, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Xie, Chuy, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Lu, Meihua, Department of General Practice,BaNan Hospital of chongqing Medical University, Chongqing, Chongqing, China
  • Zhang, Dengyang, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Zhao, Yuming, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Chen, Jiasi, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Zheng, Zhihua, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Chen, Yun, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China
  • Zhao, Zhizhuang Joe, Department of Pathology, University of Oklahoma Health Sciences Center, Lindsay, Oklahoma, United States
Background

Dendritic cells (DC) are involved in the recovery process of acute kidney injury disease (AKD). Lymphoid DC development is critically dependent on Fms-like tyrosine kinase receptor 3 ligand (Flt3L) in vivo. However, the role of Flt3L in the maintenance of kidney DC and the outcome of AKD are not defined. We hypothesized that Flt3L might improve the tubular recovery after AKD by fostering the accumulation of DC.

Methods

Blood were collected from patients of prerenal or renal AKD and healthy controls. Wild type mice and IRF8KO mice were treated with 15μg rFlt3L or 10mg/kg Flt3 inhibitor gilteritinib. They were subjected to ischemia-reperfusion (IR) to induce post-ischemic AKD or were injected with 15mg/kg cisplatin to induce nephrotoxic AKD. Serum and kidneys were collected. Kidney function, tubular injury, primary/proximal tubular cell numbers were quantified.

Results

Initially, we observed an increased level of serum Flt3L in patients with AKD. Further analysis revealed that this increase was specific for trauma- rather than heart failure- or sepsis-induced AKD. A similar increase in serum Flt3L was found in mice with IR-AKD but not cisplatin-induced AKD. This was accompanied by reduced blood DC but increased kidney DC in mice after IR-AKD. The numbers of type I conventional dendritic cell (cDC1) and CD64+DC in kidney were significantly decreased in gilteritinib-treated IR-AKD mice, which were associated with more severe tubular injury. With reduced kidney cDC1, IRF8KO mice also showed worsen kidney injury and aggravated functional failure upon IR-AKD. Therapeutic administration of rFlt3L significantly increased kidney cDC1 and CD64+DC upon IR-AKD in wild type but not IRF8KO mice. This was associated with reduced tubular injury, enhanced proliferation activity of tubular cells, and decreased expression of tubular injury markers (Ngal, Timp-2, Igfbp-7 and Hgf) in kidney of wild type mice. In addition, pre-treatment of wild type mice with rFlt3L increased kidney cDC1 and protected the mice from severe IR-AKD.

Conclusion

Flt3L is upregulated in humans and mice during IR-AKD. It fosters the accumulation of kidney cDC1 and CD64+DC, thereby limiting the severity of kidney injury in mice. The current study implies the possibility of DC-based immunotherapy for treatment of AKD.