{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:48:24Z","timestamp":1791726504144,"version":"4.3.4"},"reference-count":96,"publisher":"American Society for Clinical Investigation","issue":"4","funder":[{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["DK090728"],"award-info":[{"award-number":["DK090728"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,27]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>\n                      Pkd1\n                      <jats:sup>RC\/RC<\/jats:sup>\n                    <\/jats:italic>\n                    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.\n                    <jats:italic>Pappa<\/jats:italic>\n                    deficiency effectively inhibited the development of cysts in the\n                    <jats:italic>\n                      Pkd1\n                      <jats:sup>RC\/RC<\/jats:sup>\n                    <\/jats:italic>\n                    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\n                    <jats:italic>\n                      Pkd1\n                      <jats:sup>RC\/RC<\/jats:sup>\n                    <\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.135700","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T16:33:51Z","timestamp":1580229231000},"source":"Crossref","is-referenced-by-count":35,"title":["Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis"],"prefix":"10.1172","volume":"5","author":[{"given":"Sonu","family":"Kashyap","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Robert and Arlene Kogod Center on Aging,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyaw Zaw","family":"Hein","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Robert and Arlene Kogod Center on Aging,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia 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