Abstract: FR-OR110

Smad Anchor for Receptor Activation (SARA) Overexpression in Pericytes Prevents Renal Fibrosis

Session Information

Category: Cell Biology

  • 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion


  • Hayashida, Tomoko, Northwestern University, Chicago, Illinois, United States
  • Han, Zhe, Children's National Medical Center, Washington, District of Columbia, United States
  • Runyan, Constance, Northwestern University, Chicago, Illinois, United States
  • Schnaper, H. William, Northwestern University, Chicago, Illinois, United States
  • Liang, Xiaoyan, Northwestern University, Chicago, Illinois, United States

We previously reported that overexpressing SARA in cultured proximal tubular epithelial cells prevents transforming growth factor (TGF)-β-induced mesenchymal phenotypic transition, and SARA knockdown alone is sufficient to induce such changes, suggesting that SARA is critical for maintenance of cellular phenotype. Here we tested whether maintaining SARA levels could ameliorate mouse and fly models of kidney fibrosis.


A SARA-overexpressing (SARA-Tg) mouse was generated by inserting full-length human cDNA for SARA1 preceded by a lox-stop-lox cassette at the ROSA26 locus, and was crossed with either PDGFRβ-Cre or tamoxifen-inducible Cre-ERT2 mice to induce ectopic SARA expression specifically in pericytes or systemically, respectively. Aristolochic acid (AA), 5 mg/kg, was given intraperitoneally 3x week for 4 weeks beginning at 8 weeks old, to SARA Tg-Cre mice and their Cre-negative littermates. The mice were sacrificed for analysis one week after AA treatment was stopped. Drosophila heart tube/nephrocyte fibrosis model was generated using a 4xHand-Gal4 driver and iRNA for Wds or Ada2b.


Severe interstitial fibrosis was observed in wild-type mice subjected to AA and whole-kidney SARA expression was significantly lower than in non-AA control mice. On the other hand, SARA levels remained similar even after AA administration to SARA-Tg Cre-ERT2 mice treated with tamoxifen. Cre expression in PDGFRβ-Cre mice starts approximately at E12.5, but SARA-Tg PDGFRβ-Cre mice developed normally and were fertile. PDGFRβ-Cre expression was detected in pericytes and in some mesangial cells as expected. AA-induced fibrosis as detected by COL1A2 and α-smooth-muscle actin staining and mRNA levels were significantly less in PDGFRβ-Cre+ SARA-Tg mice compared to their Cre-negative littermates. In Drosophila, cardioblast/nephrocyte-specific knockdown of Wds or Ada2b caused fibrosis around the heart tube as shown by increased pericardin expression. SARA knockdown significantly enhanced, and SARA overexpression virtually prevented, pericardin expression.


SARA maintains renal cell phenotype in murine kidney disease and decreases the collagen-producing response in mice and flies. Our data support the recent findings by others that pericytes are essential for renal fibrosis, and suggest a role for SARA in ameliorating fibrogenesis.


  • NIDDK Support