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Abstract: FR-PO262

CD74 Promotes Cyst Growth and Interstitial Fibrosis in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Zhou, Xia, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Li, Xiaoyan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Agborbesong, Ewud, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized with cyst formation, inflammation and renal fibrosis. CD74 has been recognized as a transmembrane receptor for the cytokine macrophage migration inhibitory factor (MIF). Our previous study has reported that MIF is an important regulator of cyst growth in ADPKD possibly through binding with CD74 to activate ERK, PI3K-Akt, NF-kappa B and AMPK pathways to regulate the cell proliferation and survival. However, whether and how CD74 by itself regulates cyst growth and interstitial fibrosis remains elusive.


To understand the role of CD74 in vivo, we generated Pkd1flox/flox:CD74-/-:Pkhd1-Cre mice. To explore the mechanisms mediated by CD74 in regulating cyst growth, inflammation and renal fibrosis, we knocked down CD74 with siRNA and inhibited MIF with its inhibitor ISO-1 in renal epithelial cells and fibroblasts.


We found that CD74 were upregulated in Pkd1 mutant cells and kidneys, and knockout of CD74 delayed cyst growth as seen by decreased cystic index, kidney weight /body weight ratios, blood urea nitrogen levels in Pkd1flox/flox:Pkhd1-Cre mice. Deletion of CD74 decreased proliferation and increased apoptosis of cyst lining epithelia, reduced the recruitment of macrophages in pericystic and interstitial areas, and ameliorated interstitial fibrosis. Knockout of CD74 decreased mRNA levels of MCP-1, TNF alpha, MIF and CD44 as well as fibrotic markers, including Col I, Col III, and fibronectin. In addition, we found that knockdown of CD74 by siRNA decreased the expression of those cytokines, CD44, and fibrotic markers in Pkd1 mutant renal epithelial cells and renal fibroblasts. Our ChIP assay indicated that CD74 regulated the transcription of those genes through binding on their promoters, supporting a feedback loop between MIF and CD74. Furthermore, we found that inhibition of MIF with its inhibitor ISO-1 decreased the phosphorylation of ERK, Akt and S6, and blocked the phosphorylation of Smad3 induced by TGF beta in renal fibroblasts.


CD74 promotes cyst growth and renal interstitial fibrosis in ADPKD. This study identifies novel transcriptional targets of CD74, including cytokine and fibrotic markers, which will help in understanding of essential pathways regulating cystic cell growth and survival, the recruitment of macrophages and the activation of renal fibroblasts in ADPKD.


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