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

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

doi:10.1172/jci.insight.135700

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.

Highlights

Autosomal dominant polycystic kidney disease (ADPKD) is a chronic kidney disease characterized by fluid-filled cysts in renal tubules
As in the Pkd1RC/RC mice, Pappa expression was increased in the kidney of Pkd2WS25/– mice, suggesting that Pregnancy-associated plasma protein A (PAPP-A) could be a component of the pathogenesis of ADPKD in both murine models (Figure 1D)
Given that the in vitro data suggested a role for the PKA pathway in regulation of PAPP-A in ADPKD, we further examined this possibility in vivo using the Pkd1RC/RC mouse model with kidney-specific overactivation of PKA [71]

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is a chronic kidney disease characterized by fluid-filled cysts in renal tubules. Progressive growth and expansion of these cysts often leads to end-stage renal disease (ESRD). It is caused mainly by mutations in PKD1 or PKD2, which encode polycystin-1 (PC-1) and PC-2, respectively [1]. This is a systemic disorder that is characterized primarily by the bilateral formation of fluid-filled renal cysts, as well as extrarenal manifestations. Progressive enlargement of renal cysts over time leads to chronic renal injury and often renal failure. A better understanding of the pathophysiology of ADPKD is necessary for the development of more effective therapies for the management of this systemic disease

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Results

Conclusion