Kidney Week

Abstract: FR-PO407

Proximal Tubular Uptake of Free Fatty Acid (FFA) by Kidney Injury Molecule-1 (KIM-1) Mediates Tubulointerstitial Disease in Diabetic Mice

Session Information

• Diabetic Kidney Disease: Basic - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Mori, Yutaro, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Yutaro Mori,

• Chang, Jae Hyung, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Jae Hyung Chang,

• Mou, Shan, Brigham and Women's Hospital, Harvard Medical School, Brookline, United States

Shan Mou,

• Zhao, Huiping, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Huiping Zhao,

• Li, Jiahua, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Jiahua Li,

• Galichon, Pierre, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Pierre Galichon,

• Brooks, Craig R., Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Craig R. Brooks,

• Xiao, Sheng, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Sheng Xiao,

• Sabbisetti, Venkata, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Venkata Sabbisetti,

• Palmer, Suetonia, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Suetonia Palmer,

• Kuchroo, Vijay K., Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Vijay K. Kuchroo,

• Ichimura, Takaharu, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Takaharu Ichimura,

• Bonventre, Joseph V., Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States

Joseph V. Bonventre,

Background

Diabetic kidney disease (DKD) is associated with tubulointerstitial damage which predicts progression of chronic kidney disease. KIM-1, a scavenger receptor, is the most upregulated proximal tubule protein in many forms of kidney injury. Dysregulated lipid metabolism is a primary feature of DKD. We hypothesized that KIM-1-mediated uptake of FFAs contributes to tubulointerstitial damage in DKD.

Methods

Renal epithelial cells expressing KIM-1 (LLC-PK1 cells and mouse primary renal epithelial cells) were exposed to palmitate followed by measurement of FFA uptake, cell death and pro-inflammatory and pro-fibrotic effects in vitro. In vivo, two animal models were used to evaluate the role of KIM-1-mediated FFA uptake. A DKD model induced by unilateral nephrectomy, streptozotocin and high fat diet (UNx-STZ-HFD DKD) was studied in wild-type or KIM-1^Δmucin (functional knockout of KIM-1 lacking a mucin domain) mice. A second new model was created whereby KIM-1 or KIM-1^Δmucin was upregulated by aristolochic acid and the effect of subsequent injection of FFA was determined (AA-FFA model).

Results

FFA was taken up by the wild-type KIM-1 expressing cells but not by control or KIM-1^Δmucin expressing cells, leading to cell death in cells expressing wild-type KIM-1. mRNAs of IL-1β and NLRP3 were increased after FFA treatment only in cells expressing wild-type KIM-1 but not controls. Conditioned media harvested from FFA-treated cells expressing wild-type KIM-1 stimulated greater αSMA expression in mouse fibroblasts, compared to media from KIM-1^Δmucin cells. In the UNx-STZ-HFD DKD model, wild-type mice showed greater proximal tubular atrophy, macrophage infiltration, fibrosis and albuminuria when compared with KIM-1^Δmucin mice. In the AA-FFA model, wild-type mice showed more macrophage infiltration, αSMA expression and loss of brush border when compared with KIM-1^Δmucin mice.

Conclusion

KIM-1 mediates the proximal tubular uptake of FFA, which leads to cell death and pro-inflammatory and pro-fibrotic responses in diabetic mice. Our findings support the role of KIM-1 as a therapeutic target for DKD.

Funding

• NIDDK Support