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Abstract: FR-PO119

Breast Regression Protein-39 (BRP-39) Promotes Fibrosis Following AKI by Inducing Matrix Expression by PDGFRβ+ Myofibroblasts

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms


  • Chinnadurai, Amirtha, Yale University School of Medicine, New Haven, Connecticut, United States
  • Xu, Leyuan, Yale University, New Haven, Connecticut, United States
  • Cantley, Lloyd G., Yale University School of Medicine, New Haven, Connecticut, United States

Maladaptive repair after unilateral ischemia-reperfusion injury (U-IRI) leads to sustained low-level mRNA expression of chitinase-3-like1(Chi3l1, protein name BRP-39). We have recently shown that persistent expression of BRP-39 promotes interstitial fibrosis following maladaptive kidney repair. At the whole kidney level, PDGFRβ+ myofibroblast accumulation was not significantly different in the injured wild-type (WT) and Brp-39 knockout. However, there was a significant decrease in the expression of collagen 1α1(Col1a1), collagen 3α1(Col3a1) and fibronectin(Fn1) by myofibroblasts in the injured kidney of BRP-39 knockout compared to the WT kidney. Here,we investigated the role of BRP-39 in PDGFRβ+ myofibroblast matrix gene expression during the acute kidney injury(AKI) to chronic kidney disease transition.


Male WT mice (9–11 weeks) subjected to U-IRI for 30 minutes. The injured kidney was removed on day 14 after U-IRI, and primary renal myofibroblasts were isolated via magnetic activated cell sorting using PE-tagged PDGFRβ antibody. Purity of the PDGFRβ+ myofibroblasts assessed by qPCR for PDGFRβ mRNA. Primary myofibroblasts were grown for 4 days in culture (~70% confluence), then stimulated with recombinant BRP-39 (0.5 μg/ml) or vehicle control for 24-hour followed by qPCR for Col1a1, Col3a1 and Fn1.


Primary PDGFRβ+ myofibroblasts were enriched 5.7fold compared to the initial population(n=7,p=0.04) and were also enriched for expression of the postulated BRP-39 profibrotic receptor, Crth2 (n=7, p=0.004). The expression level of Pdgfrb and Crth2 in these cells were 9.1 and 3.7fold higher than in immortalized fibroblast cell lines (NRK49 and NIH3T3). Stimulation of PDGFRβ+ myofibroblasts with BRP39 resulted in 3.4fold in Fn1 expression(p=0.038,n=6) with no significant effect on Col1a1 or Col3a1. Preliminary findings (n=2, pooled from 8 kidneys) show with the addition of TGFβ1 (20 ng/ml) and PDGFβ (10 ng/ml) with BRP39 resulted in a further increase in fibronectin expression (dct = 8.489±5.22 vs 3.34±4.62)


We show that freshly isolated myofibroblasts express high levels of the profibrotic receptor,crth2 and directly respond to BRP39 by increasing fibronectin expression. These in-vitro findings suggest that BRP39 and/or the crth2 receptor may serve as therapeutic targets to limit fibrosis after AKI


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