Metalloproteinase PAPP - A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

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  • Sonu Kashyap, Mayo Clinic Rochester, MN
  • ,
  • Kyaw Zaw Hein, Mayo Clinic Rochester, MN, Rush University
  • ,
  • Claudia C.S. Chini, Mayo Clinic Rochester, MN
  • ,
  • Jorgo Lika, Mayo Clinic Rochester, MN
  • ,
  • Gina M. Warner, Mayo Clinic Rochester, MN
  • ,
  • Laurie K. Bale, Mayo Clinic Rochester, MN
  • ,
  • Vicente E. Torres, Robert M. and Billie Kelley Pirnie Translational PKD Center
  • ,
  • Peter C. Harris, Robert M. and Billie Kelley Pirnie Translational PKD Center
  • ,
  • Claus Oxvig
  • Cheryl A. Conover, Mayo Clinic Rochester, MN
  • ,
  • Eduardo N. Chini, Mayo Clinic Rochester, MN

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage renal disease (ESRD). The treatment options for ADPKD are limited. We observed an upregulation in several IGF-1 pathway genes in the kidney of Pkd1RC/RC mice, a model of ADPKD. Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that cleaves inhibitory IGF binding proteins (IGFBPs), increasing the local bioactivity of IGF-1, was highly induced in the kidney of ADPKD mice. PAPP-A levels were high in cystic fluid and kidneys of humans with ADPKD. Our studies further showed that PAPP-A transcription in ADPKD was mainly regulated through the cAMP/CREB/CBP/p300 pathway. Pappa deficiency effectively inhibited the development of cysts in the Pkd1RC/RC mice. The role of PAPP-A in cystic disease appears to be regulation of the IGF-1 pathway and cellular proliferation in the kidney. Finally, preclinical studies demonstrated that treatment with a monoclonal antibody that blocks the proteolytic activity of PAPP-A against IGFBP4 ameliorated ADPKD cystic disease in vivo in Pkd1RC/RC mice and ex vivo in embryonic kidneys. These data indicated that the PAPP-A/IGF-1 pathway plays an important role in the growth and expansion of cysts in ADPKD. Our findings introduce a therapeutic strategy for ADPKD that involves the inhibition of PAPP-A.

Original languageEnglish
Article numbere135700
JournalJCI Insight
Volume5
Issue4
Number of pages18
DOIs
Publication statusPublished - 2020

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