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Kidney Week

Abstract: TH-OR019

Smad Anchor for Receptor Activation (SARA) Prevents Pericyte Activation and Protects Kidney from Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms


  • Liang, Xiaoyan, Northwestern University, Chicago, Illinois, United States
  • Schnaper, H. William, Northwestern University, Chicago, Illinois, United States
  • Humphreys, Benjamin D., Washington University School of Medicine, Clayton, Missouri, United States
  • Hayashida, Tomoko, Northwestern University, Chicago, Illinois, United States

Pericytes are a major source of fibrogenic cells in injured kidneys. We previously reported that decreasing SARA expression drives cultured proximal tubular epithelial cell dedifferentiation to a pro-fibrotic phenotype, and last year at ASN showed that pericyte-specific overexpression of SARA prevents interstitial fibrosis induced by aristolochic acid (AA) in mice. Here, we characterize the actions of SARA in pericytes.


Conditional human SARA-overexpressing mice were bred with PDGFRβ-Cre mice to drive pericyte SARA expression. The offspring were further bred with Z/EGFP or COL1A1-GFP mice to mark cells where Cre or type I collagen transcription is active, respectively. Mice were given AA (2.5 mg/kg, i.p., 3x week, for 3 weeks), then sacrificed after 3 more weeks. Harvested kidneys were enzymatically digested and sorted for GFP+ cells to obtain pericytes that were analyzed by flow cytometry and qPCR. A pericyte line (Gli1+-iPeri) was isolated from a Gli1+ tdTomato Immortomouse.


As anticipated, native SARA mRNA expression was 62% decreased after AA treatment in GFP+ cells isolated from both phenotypically wild-type (SARAWT; PDGFRβ-Cre+; Z/EGFP) and SARA-overexpressing (SARATg; PDGFRβ-Cre+; Z/EGFP) mice. Transgene-derived SARA was detected even after AA, only in SARATg mice. SARAWt mice showed significant expansion of the renal interstitial, GFP+ pericyte population after AA treatment, but this did not occur in mice with SARA-overexpression in pericytes. GFP+ cells isolated from wild-type mice without AA were NG2+, CD90.1-, confirming their pericyte origin. AA treatment induced 45% of the wild-type GFP+ cells to become CD90.1+, suggesting pericyte fibroblastic transition. This shift was not observed in GFP+ cells isolated from AA-treated, SARA-overexpressing mice. COL1A1 mRNA expression was incrased by 10 fold in GFP+ cells from SARAWt but not SARATg littermates. The Gli1+-iPeri cell line expressed very little SARA in culture and strongly expressed αSMA. However, transfection with SARA significantly reduced TGF-β1-induced αSMA and COL1A2 promoter activity, suggesting that re-introduction of SARA at least partially reverses the fibrotic nature of Gli1+-iPeri cells.


These data suggest that SARA expression in pericytes suppresses their activation to produce extracellular matrix.


  • NIDDK Support