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Kidney Week

Abstract: TH-OR010

Inactivation of Mtorc1 in Proximal Tubular Epithelial Cells Reduces KIM-1-Mediated Kidney Fibrosis and Inflammation in Mice

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Yin, Wenqing, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Brooks, Craig R., Vanderbilt University Medical Center/Division of Nephrology & Hpertension, Nashville, Tennessee, 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 patients to progressive chronic kidney disease (CKD). Previously we reported that persistent expression, beginning prenatally, of kidney injury molecule-1 (KIM-1) in tubule epithelial cells of the nephron causes murine kidney fibrosis through a mechanism involving mTOR. Since prenatal activation of KIM-1 in this system also decreases nephron number, we tested the hypothesis that postnatal activation of KIM-1 expression specifically in proximal tubular cells (PTCs) would lead to fibrosis independent of any potential effect on kidney development, and evaluated the role of mTOR in this context.

Methods

We created proximal tubular cell specific KIM-1 overexpression transgenic mice by treating Slc34a1CreERT2/+;CAG-Z/Kim1-APtg/+ (KIM-1PTCtg) mice with tamoxifen beginning at 4 weeks of age to express KIM-1 in proximal tubules in a postnatal, post kidney development, context. The resulting KIM-1PTCtg mice (and non-KIM-1 overexpression controls) were subjected to bilateral renal ischemia-reperfusion injury (IRI) for 26 minutes, or sham surgery, at 3 months of age and then evaluated at 3 or 6 months later for kidney fibrosis. We also created KIM-1PTCtg/RaptorPTCko mice, where mTORC1 is deleted at 4 weeks of age in KIM-1 overexpressing PTCs, using the same tamoxifen-inducible promoter, and these animals were then evaluated for kidney fibrosis with or without bilateral IRI.

Results

With tamoxifen-induced postnatal KIM-1 overexpression in proximal tubular cells, KIM-1PTCtg mice developed fibrosis with progressive renal insufficiency at 6 months of age. Bilateral IRI in KIM-1PTCtg mice at 3 months of age caused maladaptive repair and a persistence of renal insufficiency post injury, leading to progressive kidney fibrosis and renal failure with an earlier onset (5 months of age) than sham controls. In contrast, KIM-1PTCtg/RaptorPTCko mice subjected to bilateral IRI had less kidney fibrosis and a reduced inflammatory response, demonstrating a role for mTOR in the fibrotic response.

Conclusion

Persistent expression of KIM-1 may play an important role on the link between AKI and progressive CKD. mTORC1 is a potential therapeutic target in KIM-1-mediated kidney injury and fibrosis in mice.

Funding

  • NIDDK Support