Kidney Week

Abstract: TH-PO112

GDF15 Marked Stressed Tubular Epithelium and Alleviated Ischemic AKI

Session Information

• AKI: Inflammation, New Technologies, Omics
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Liu, Jing, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States

Jing Liu,

• Kumar, Sanjeev, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States

Sanjeev Kumar,

• Gao, Michael, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States

Michael Gao,

• Guo, Jinjin, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States

Jinjin Guo,

• Cippa, Pietro E., Keck School of Medicine of the University of Southern California, Los Angeles, California, United States

Pietro E. Cippa,

• McMahon, Andrew P., Keck School of Medicine of the University of Southern California, Los Angeles, California, United States

Andrew P. McMahon,

Background

Renal ischemia reperfusion injury (IRI) frequently triggers tubular damage leading to acute kidney injury (AKI) in varied clinical settings including kidney transplantation. We identified Gdf15 (Growth/differentiation factor 15) as one of the genes rapidly activated in the mouse nephron following ischemic AKI; a similar induction is observed after transplant of the human kidney. First identified as an autocrine regulatory molecule associated with macrophage activation, Gdf15 was induced by proinflammatory cytokines and activated by various stressors including inflammation, oxidative stress and DNA damage. The role for endogenous GDF15 in ischemic kidneys is unclear.

Methods

To study Gdf15 expression and function in the mouse kidney, we generated a mouse line (Gdf15^nuGFP-CE)producing a truncated GDF15 missing C-term 210 a.a. and fused with P2A-nuclearGFP-F2A-CREERT2. We examined GFP and tamoxifen dependent TDT expression in Gdf15^{nuGFP-CE/ +}, R26^TDT/+ mice and compared the acute and chronic renal response to IRI in Gdf15 heterozygous and Gdf15 null mice by qRT-PCR, histology and immunofluorescence. To validate the clinical relevance of our findings, we performed a GDF15-related single nucleotide polymorphism association study in a cohort of kidney transplant recipients.

Results

In steady state, GDF15 was produced mainly by the Apq1- thin descending limb of the Henle’s loop (tDLH), by the S3 segment of the proximal tubule and by principal cells in the collecting duct. After moderate bilateral renal IRI, Gdf15 was predominantly activated in proximal tubules, Aqp1+ tDLH, principal cells in the collecting ducts and connecting tubules. Moreover, GDF15 deficiency exacerbated acute tubular injury, enhanced inflammatory response and facilitated adaptive immunity following ischemia. Consistently with the immune-regulatory effect observed in the mouse model, we found that single nucleotide polymorphisms previously linked to lower circulating GDF15 concentration, were associated with an increased incidence of biopsy proven acute rejection in the first year after kidney transplantation.

Conclusion

GDF15 is a functionally relevant, conserved element with reno-protective and immune-regulatory properties in the immediate response to ischemic AKI.

Funding

• Other U.S. Government Support