Kidney Week

Abstract: TH-PO505

Dicer Promotes Renal Recovery and Limits Interstitial Fibrosis Following Kidney Injury

Session Information

• CKD: Mechanisms - I
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• Lin, Jamie, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Jamie Lin,

• Lovisa, Sara, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Sara Lovisa,

• Zeisberg, Michael, Univ Med Center of Goettingen, Goettingen, Germany

Michael Zeisberg,

• Sugimoto, Hikaru, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Hikaru Sugimoto,

• Xiao, Fei, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Fei Xiao,

• Calin, George, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

George Calin,

• Lebleu, Valerie, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Valerie Lebleu,

• Kalluri, Raghu, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Raghu Kalluri,

Background

Renal tubulointerstitial fibrosis is the histopathological hallmark observed in chronic kidney disease; and activated fibroblasts, myofibroblasts, are the dominant extracellular matrix-producing cells that contribute to fibrosis development. Dysregulation or deletion of Dicer, a ribonuclease involved in microRNA (miRNA) generation, impacts kidney health and function. Since fibroblasts are key cells responsible for renal fibrosis, we investigated whether Dicer might effect myofibroblast and fibrosis formation by deletion of Dicer from myofibroblasts in vivo.

Methods

Dicer^fl/fl mice were crossed with α-smooth muscle actin promoter (αSMA^Cre) mice, a marker of activated fibroblast, to generate WT (αSMA^Cre–;Dicer^fl/fl) and Dicer conditional knock-out mice (αSMA^Cre+;Dicer^fl/fl, hereafter Dicer^cKO). Mice were challenged to three different kidney injury models. MiRNAs from primary kidney fibroblasts were analyzed.

Results

Isolated human and mouse fibroblast from fibrotic kidneys demonstrated increased Dicer hypermethylation. Dicer^cKO mice had no overt renal abnormalities. To determine whether deletion of Dicer in myofibroblast might impact the development of tubulointerstitial fibrosis, both WT and Dicer^cKO mice underwent unilateral ureteral obstruction, nephrotoxic serum nephritis, and folic acid kidney injury. Dicer^cKO mice displayed increased collagen deposition and tubulointerstitial fibrosis compared to WT animals in all three models. Furthermore, loss of Dicer resulted in an increase of proliferating, Ki67 positive, αSMA⁺ myofibroblasts. MiRNA array analysis of primary mouse fibroblasts from the UUO kidneys of Dicer^cKO and WT mice revealed a differential expression of several miRNAs, including upregulation of miR-451, a Dicer-independent miRNA, in the Dicer^cKO mice.

Conclusion

Renal tubulointerstitial fibrosis is the pathological sequelae observed in chronic injury. Dicer is critically involved in kidney homeostasis, and here we show that Dicer deletion in myofibroblasts resulted in differential miRNA expression and pathologic myofibroblast proliferation perpetuating fibrogenesis. Depletion of Dicer and associated miRNAs is pathogenic in various kidney injury models and accelerates kidney failure.