Abstract: TH-PO230

Proximal Tubular Epithelial Expression of Kim-1 Causes Progressive Kidney Injury in Mice

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Yin, Wenqing, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Valerius, M. Todd, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Acute kidney injury (AKI) predisposes to the progression of chronic kidney disease (CKD) and the development of end stage renal failure. Previously, we had reported that early and persistent epithelial expression in nephrons of kidney injury molecule-1 (KIM1) causes murine kidney fibrosis, and zebrafish tubule damage through a mechanism involving mTOR. Since prenatal activation also decreases nephron number we tested the hypothesis that postnatal activation of KIM-1 expression specifically in renal proximal tubular epithelial cells would lead to fibrosis independent of any potential effect on kidney development.

Methods

We created proximal tubular cell specific KIM-1 transgenic mice by treating the Slc34a1 Cre-ERT2 mouse with tamoxifen to express KIM-1 in proximal tubules in a postnatal context. The resulting KIM-1PTCtg transgenics (and non-KIM1 expressing controls) were subjected to bilateral renal ischemia-reperfusion injury for 26 minutes or sham surgery.

Results

KIM-1 was expressed on the proximal tubular cells after tamoxifen-induced Cre-ERT2 recombination starting at 4 weeks of age. Without any further intervention KIM-1PTCtg mice developed fibrosis with progressive renal insufficiency at 6 months of age, while the kidney function and histology were close to normal at 3 months of age. Bilateral renal ischemia reperfusion injury in KIM-1PTCtg kidneys at 3 months of age cause impaired repair with remained renal insufficiency, leading to progressive kidney fibrosis and renal failure.

Conclusion

Chronic activation of KIM-1 expression promotes kidney fibrosis and accelerates the progression of chronic kidney disease after acute kidney injury. Persistent expression of KIM-1 may play an important role on the link between acute kidney injury and progressive chronic kidney disease.

Funding

  • NIDDK Support