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

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

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

I: JCI Insight, Bind 5, Nr. 4, e135700, 2020.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Harvard

Kashyap, S, Hein, KZ, Chini, CCS, Lika, J, Warner, GM, Bale, LK, Torres, VE, Harris, PC, Oxvig, C, Conover, CA & Chini, EN 2020, 'Metalloproteinase PAPP - A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis', JCI Insight, bind 5, nr. 4, e135700. https://doi.org/10.1172/jci.insight.135700

APA

Kashyap, S., Hein, K. Z., Chini, C. C. S., Lika, J., Warner, G. M., Bale, L. K., Torres, V. E., Harris, P. C., Oxvig, C., Conover, C. A., & Chini, E. N. (2020). Metalloproteinase PAPP - A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. JCI Insight, 5(4), [e135700]. https://doi.org/10.1172/jci.insight.135700

Author

Kashyap, Sonu ; Hein, Kyaw Zaw ; Chini, Claudia C.S. ; Lika, Jorgo ; Warner, Gina M. ; Bale, Laurie K. ; Torres, Vicente E. ; Harris, Peter C. ; Oxvig, Claus ; Conover, Cheryl A. ; Chini, Eduardo N. / Metalloproteinase PAPP - A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. I: JCI Insight. 2020 ; Bind 5, Nr. 4.

Bibtex

@article{2af644dec611456c9252f0f41b53dcf3,

title = "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.",

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

year = "2020",

doi = "10.1172/jci.insight.135700",

language = "English",

volume = "5",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "4",

}

RIS

TY - JOUR

T1 - Metalloproteinase PAPP - A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

AU - Kashyap, Sonu

AU - Hein, Kyaw Zaw

AU - Chini, Claudia C.S.

AU - Lika, Jorgo

AU - Warner, Gina M.

AU - Bale, Laurie K.

AU - Torres, Vicente E.

AU - Harris, Peter C.

AU - Oxvig, Claus

AU - Conover, Cheryl A.

AU - Chini, Eduardo N.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85081645384&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.135700

DO - 10.1172/jci.insight.135700

M3 - Journal article

C2 - 31990681

AN - SCOPUS:85081645384

VL - 5

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 4

M1 - e135700

ER -