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

• AKI: New Players and New Mechanisms
  October 25, 2018 | Location: 6D, San Diego Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Yin, Wenqing, Brigham and Women's Hospital, Boston, Massachusetts, United States

Wenqing Yin, MD, PhD



Wenqing Yin, MD/PhD I joined Dr. Bonventre's laboratory at Brigham and Women's Hospital of Harvard Medical School since 2011 as a PhD student. My research project was focused on defining the role of KIM-1-mediated pathomechanisms for the development of chronic kidney disease by using transgenic animal models. My work revealed a previously unknown link between KIM-1 and aberrant mTOR-signaling in the pathogenesis of chronic kidney disease. These findings have significant translational relevance and uncovered novel therapeutic roles of mTOR inhibitors for the treatment of chronic kidney disease (Yin et al., 2016, J Am Soc Nephrol). I am currently a PGY4, renal fellow at Boston Medical Center, Boston University School of Medicine.

• Brooks, Craig R., Vanderbilt University Medical Center/Division of Nephrology & Hpertension, Nashville, Tennessee, United States

Craig R. Brooks,

• Valerius, M. Todd, Brigham and Women's Hospital , Boston, Massachusetts, United States

M. Todd Valerius,

• Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States

Joseph V. Bonventre,

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 Slc34a1^CreERT2/+;CAG-Z/Kim1-AP^tg/+ (KIM-1^PTCtg) 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-1^PTCtg 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-1^PTCtg/Raptor^PTCko 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-1^PTCtg mice developed fibrosis with progressive renal insufficiency at 6 months of age. Bilateral IRI in KIM-1^PTCtg 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-1^PTCtg/Raptor^PTCko 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