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Abstract: FR-OR115

Proximal Tubular Uptake of Free Fatty Acid (FFA) by Kidney Injury Molecule-1 (KIM-1) Mediates Tubulointerstitial Damage in Diabetic Kidney Disease (DKD), Which Is Attenuated by a Novel Inhibitor

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Mori, Yutaro, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ajay, Amrendra Kumar, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Chang, Jae Hyung, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Zhao, Huiping, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Kishi, Seiji, Tokushima University, Tokushima, Tokushima, Japan
  • Li, Jiahua, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Galichon, Pierre, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Brooks, Craig R., Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Xiao, Sheng, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Sabbisetti, Venkata, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Palmer, Suetonia, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Henderson, Joel M., Boston University School of Medicine, Boston, Massachusetts, United States
  • Ichimura, Takaharu, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

DKD is associated with tubulointerstitial damage. KIM-1, a scavenger receptor, is the most upregulated proximal tubule protein in many forms of kidney injury. Dyslipidemia is a primary feature of DKD. We hypothesized that KIM-1-mediated uptake of FFAs contributes to tubulointerstitial damage in DKD.

Methods

Human DKD renal biopsy samples were analyzed. Renal epithelial cells expressing KIM-1 (LLC-PK1 cells overexpressing KIM-1, and mouse and human primary cells) were exposed to palmitate followed by measurement of FFA uptake, cell death and pro-inflammatory and pro-fibrotic effects determined in vitro. To clarify the role of FFA uptake by KIM-1 in vivo, a DKD model induced by unilateral nephrectomy, streptozotocin and high fat diet (UNx-STZ-HFD) was studied in wild-type (WT) or KIM-1Δmucin (functional knockout of KIM-1) mice. A second new model was created whereby KIM-1 was upregulated by aristolochic acid and the effect of subsequent injection of FFA was determined (AA-FFA model). An inhibitor for KIM-1-mediated endocytosis was screened from >14,000 compounds and tested both in vitro and in vivo.

Results

KIM-1 expression in DKD patients was positively correlated with tubulointerstitial inflammation and fibrosis. FFA was taken up by the WT-KIM-1 expressing cells causing IL-1β production through activation of inflammasomes and cell death. Conditioned media from FFA-treated WT cells stimulated greater αSMA expression in mouse fibroblasts, than did media from KIM-1Δmucin cells. In the UNx-STZ-HFD model, WT mice showed greater proximal tubular atrophy, macrophage infiltration, fibrosis and albuminuria than KIM-1Δmucin mice. In the AA-FFA model, WT mice showed more macrophage infiltration, αSMA expression and loss of brush border than KIM-1Δmucin mice. Both in vitro and in vivo our newly identified compound prevented FFA uptake and injury only on WT, not on KIM-1Δmucin.

Conclusion

KIM-1 mediates the proximal tubular uptake of FFA, leading to pro-inflammatory and pro-fibrotic responses and increase in cell death. Our findings support the role of KIM-1 as a target for DKD and introduce a new candidate therapeutic agent.

Funding

  • NIDDK Support