Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis
Sonu Kashyap, Kyaw Zaw Hein, Claudia C.S. Chini, Jorgo Lika, Gina M. Warner, Laurie K. Bale, Vicente E. Torres, Peter C. Harris, Claus Oxvig, Cheryl A. Conover, Eduardo N. Chini
Sonu Kashyap, Kyaw Zaw Hein, Claudia C.S. Chini, Jorgo Lika, Gina M. Warner, Laurie K. Bale, Vicente E. Torres, Peter C. Harris, Claus Oxvig, Cheryl A. Conover, Eduardo N. Chini
View: Text | PDF
Research Article Nephrology

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

Abstract

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.

Authors

Sonu Kashyap, Kyaw Zaw Hein, Claudia C.S. Chini, Jorgo Lika, Gina M. Warner, Laurie K. Bale, Vicente E. Torres, Peter C. Harris, Claus Oxvig, Cheryl A. Conover, Eduardo N. Chini

×

Figure 5

The role of PAPP-A in the pathogenesis of ADPKD.

Options: View larger image (or click on image) Download as PowerPoint
The role of PAPP-A in the pathogenesis of ADPKD. Western blot analysis o...
Western blot analysis of (A) p-IGFR1/IGFR1 (B) PCNA, (C) p-ERK/ERK and p-Akt/Akt, and (D) p-AMPK/AMPK in kidney tissues of 2.5- or 4.5-month-old Pkd1RC/RC Pappa+/+ and Pkd1RC/RC Pappa–/– mice. Graphs show quantitative analysis of bands by densitometry. (E) Photomicrographs showing that IGF-1 supports cystic growth in a metanephric model of cystogenesis. Day 13.5 embryonic kidneys from WT mice were stimulated with FSK (10 μM) alone (no growth hormone added) or with FSK in the presence of IGF-1 (100 ng/mL). Scale bars: 1 mm. (F) Embryonic kidneys were treated with FSK (10 μM), IGF-1 (100 ng/ml), and IGFBP4 (26 nM) in the presence or absence of mAb-PA (320 pM). IGF-1 was incubated with IGFBP4 prior to treatment. For metanephric culture, the experiment was repeated twice; n = 3 for each experiment. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test (1-tailed for D). Scale bars: 1 mm.