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Updated: Dec 29, 2025

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
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Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Sonu Kashyap1, Kyaw Zaw Hein1, Claudia Cs Chini1

  • 1Department of Anesthesiology and Robert and Arlene Kogod Center on Aging.

JCI Insight
|January 29, 2020
PubMed

Insights

Autosomal dominant polycystic kidney disease (ADPKD) involves increased Pregnancy-associated plasma protein A (PAPP-A), which drives cyst growth. Inhibiting PAPP-A activity offers a potential new therapy for ADPKD.

Area of Science:

  • Nephrology
  • Genetics
  • Molecular Biology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease (ESRD) with limited treatment options.
  • IGF-1 pathway gene upregulation was observed in ADPKD mouse models.
  • Pregnancy-associated plasma protein A (PAPP-A) increases local IGF-1 bioactivity by cleaving IGF binding proteins.

Purpose of the Study:

  • To investigate the role of PAPP-A in ADPKD pathogenesis.
  • To explore PAPP-A as a therapeutic target for ADPKD.

Main Methods:

  • Analysis of PAPP-A levels in ADPKD mouse models and human samples.
  • Investigating PAPP-A transcriptional regulation via the cAMP/CREB/CBP/p300 pathway.
  • Evaluating the therapeutic potential of PAPP-A inhibition using monoclonal antibodies in preclinical ADPKD models.

Main Results:

  • PAPP-A was highly induced in the kidneys of ADPKD mice and elevated in human ADPKD cystic fluid and kidneys.
  • PAPP-A deficiency ameliorated cyst development in Pkd1RC/RC mice.
  • Monoclonal antibody treatment blocking PAPP-A activity reduced ADPKD cyst progression in vivo and ex vivo.

Conclusions:

  • The PAPP-A/IGF-1 pathway is crucial for ADPKD cyst growth and expansion.
  • Inhibiting PAPP-A's proteolytic activity presents a promising therapeutic strategy for ADPKD.

Keywords:
Molecular pathologyNephrology

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