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Kidney Week

Abstract: TH-PO088

TGF-β Promotes Fibrosis After Severe AKI by Enhancing Renal Macrophage Infiltration

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Chung, Sungjin, Vanderbilt University Medical Center, Nashville, United States
  • Overstreet, Jessica Marie, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Li, Yan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Gewin, Leslie S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background


TGF-β, a central mediator of renal fibrosis, signals through a heterotetrameric receptor complex composed of two type I and two type II transmembrane subunits. Although macrophages are implicated as mediators of renal fibrosis and produce TGF-β1, macrophage TGF-β1 deletion did not prevent fibrosis after severe renal I/R injury. The current studies investigated the role of macrophage TGF-β signaling in post AKI fibrosis.

Methods



Male C57BL/6 wild type (WT, Tgfbr2f/f) or LysM-Cre;Tgfbr2f/f (TGFßRII-/-) mice underwent uninephrectomy plus 29 min renal I/R and were sacrificed after 4 weeks. Both in vitro and in vivo chemotaxis assays were performed.

Results

At 4 weeks after injury, there was increased renal expression of TGF-ß1 and tubulointerstitial fibrosis in WT mice. TGFßRII-/- mice had markedly decreased renal fibrosis and decreased renal macrophages. TGF-ß is a potent chemoattractant. The in vitro chemotactic response to a known chemotaxin, f-Met-Leu-Phe, was not different between isolated bone marrow monocytes (BMMs) from WT and TGFßRII-/- mice. Although TGF-ß was also a potent chemoattractant to WT BMMs, TGFßRII-/- BMMs did not respond. The SMAD inhibitor, SIS3, markedly inhibited the chemotactic response to TGF-ß in WT BMMs, but had minimal effect in TGFßRII-/- BMMs. To confirm these findings in an in vivo setting, we utilized a chemotaxis assay using matrigel plugs. Matrigel suffused with either f-Met-Leu-Phe or TGF-ß1 was injected subcutaneously into the subscapular regions of WT or TGFßRII-/- mice. After 6 days, f-Met-Leu-Phe induced equal numbers of macrophage infiltration into the matrigel plugs of WT and TGFßRII-/- mice. TGF-ß also induced matrigel macrophage infiltration in WT mice but not in TGFßRII-/- mice. To determine macrophage infiltration into post AKI kidneys, we determined the number of PKH26 labeled BMMs infiltrating into WT kidneys for 3 days 12 days after AKI. There were significantly more PKH26 labeled WT BMMs than TGFßRII-/- BMMs.

Conclusion


Macrophage TGFßRII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophage to the injured kidney through a TGF-β/TGFßRII axis is a heretofore undescribed mechanism by which TGF-ß can mediate renal fibrosis during progressive renal injury.

Funding

  • NIDDK Support