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Abstract: SA-PO646

Unbiased Interrogation of Clinically-Indicated Biopsies Identifies Discoidin Domain Receptor Inhibition as Target for Anti-Fibrotic Therapy: Cell, Animal, and Pharmacological Intervention Studies

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Gilbert, Richard E., St. Michael's Hospital, Toronto, Ontario, Canada
  • Thai, Kerri, St. Michael's Hospital, Toronto, Ontario, Canada
  • Zhang, Yanling, St .Michael Hospital, University of Toronto, Toronto, Ontario, Canada
  • Caldwell, Lauren V., Lunenfeld Tanenbaum Research Institute, Ajax, Ontario, Canada
  • Yuen, Darren A., St. Michael's Hospital, Toronto, Ontario, Canada
Background

Regardless of etiology, most forms of kidney disease are characterized by advancing fibrosis, the extent of which correlates closely with declining kidney function. As such, fibrogenesis may be a final common pathway in kidney disease progression so that strategies to temper it may attenuate the loss of function in a broad range of kidney diseases. While most efforts at developing anti-fibrotic drugs have focused on inhibiting transforming growth factor-beta (TGF-beta) or connective tissue growth factor (CTGF), other yet unidentified mediators may also be importamt targets for therapeutic development.

Methods

RNA was extracted from 14, -80C degrees frozen, clinically-indicated kidney transplant biopsies and subjected to RNASeq analysis. Clinical data including sequential eGFR values were also collected.

Results

In addition to TGF-ß and CTGF we also found that the abundance of discoidin domain receptor (DDR) mRNA correlated closely with both the extent of fibrosis (rho=0.6, p=0.01) and rate of eGFR decline (rho=0.6, p=0.01). Since DDR is a receptor tyrosine kinase that is activated by binding to fibrillary collagen, we exposed NRK-49F renal fibroblasts (p<0.05) to type I collagen and noted that this not only led to DDR phosphorylation but also induced the de novo synthesis of collagen, identified by the incorporation of 3H-proline. We next synthesized a DDR inhibitor, 6j (Wang et al., J. Med. Chem. 2016, 59, 5911−5916), showing that it dose-dependently reduced DDR phosphorylation and 3H-proline incorporation in renal fibroblasts (p<0.05) in response to collagen I. We then conducted in vivo proof-of-concept studies in the unilateral ureteric obstruction (UUO) model of kidney fibrosis showing robust reduction in collagen III deposition at 50 mg/kg/day (p<0.05) at 7 days.

Conclusion

Merging unbiased transcriptomic analysis of clinically-indicated kidney biopsies with histopathological and clinical data can identify novel mediators of fibrogenesis. The pathophysiological relevance of the so-derived targets can then be assessed by in vitro and in vivo models as a prelude to the development of new therapies for human use that aim to slow, arrest or potentially even reverse the progression of CKD.

Funding

  • Commercial Support