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Notch receptors are synthesized as single peptides and undergo three sequential proteolytic cleavage steps before rendering an active transcription factor, the Notch intracellular domain (<jats:styled-content style=\"fixed-case\">NICD<\/jats:styled-content>). Ligand binding facilitates release of <jats:styled-content style=\"fixed-case\">NICD<\/jats:styled-content> by \u03b3\u2010secretase. Evidence for the role of the Notch pathway in kidney injury comes from studies on activation of Notch by canonical ligands in cultured cells, on inhibition\/targeting of \u03b3\u2010secretase in culture or <jats:italic>in vivo<\/jats:italic>, on genetic deletion of common Notch pathway proteins such as <jats:styled-content style=\"fixed-case\">CSL<\/jats:styled-content>, or descriptions of increased transcription of Notch target genes in kidney injury. Inhibitors of \u03b3\u2010secretase prevent fibrosis in experimental kidney injury. However, these drugs may modulate other signalling systems beyond Notch and are toxic in human trials. Information regarding the specific contribution of each receptor to kidney injury may help design better targeted therapeutic approaches. In this regard, overexpression of <jats:styled-content style=\"fixed-case\">NICD1<\/jats:styled-content>, <jats:styled-content style=\"fixed-case\">NCID2<\/jats:styled-content>, <jats:styled-content style=\"fixed-case\">NICD3<\/jats:styled-content> or <jats:styled-content style=\"fixed-case\">NICD4<\/jats:styled-content> elicits biological responses in cultured renal cells that include cell proliferation, apoptosis, and inflammatory and profibrotic responses, depending on the particular <jats:styled-content style=\"fixed-case\">NICD<\/jats:styled-content>. Furthermore, immunostaining for <jats:styled-content style=\"fixed-case\">NICD1<\/jats:styled-content>, <jats:styled-content style=\"fixed-case\">NICD2<\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">NICD4<\/jats:styled-content> suggestive of receptor activation has been observed in glomerular and tubular cells in human and experimental kidney disease. Delayed conditional Notch1 or Notch2 inactivation facilitates cyst formation, and <jats:styled-content style=\"fixed-case\">NICD1<\/jats:styled-content> overexpression in podocytes or tubular cells promotes glomerulosclerosis and interstitial fibrosis. Kidney injury is a feature of human Notch2 mutations and <jats:styled-content style=\"fixed-case\">CADASIL<\/jats:styled-content> patients with mutated Notch3 may display renal injury. Notch3\u2212\/\u2212 mice display increased sensitivity to angiotensin <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\u2010induced kidney injury but are less sensitive to tubular injury, inflammation, and fibrosis following unilateral ureteral obstruction. The recent availability of blocking antibodies specific for Notch1, Notch2, and Notch3 may help to elucidate the therapeutic potential of specific targeting of individual Notch receptors in kidney disease.<\/jats:p>","DOI":"10.1002\/path.4101","type":"journal-article","created":{"date-parts":[[2012,9,6]],"date-time":"2012-09-06T07:08:14Z","timestamp":1346915294000},"page":"266-273","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Notch3 and kidney injury: never two without three"],"prefix":"10.1002","volume":"228","author":[{"given":"Maria Dolores","family":"Sanchez\u2010Ni\u00f1o","sequence":"first","affiliation":[{"name":"Servicio de Nefrologia, IdiPAZ  Madrid 28046 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"IIS\u2010Fundaci\u00f3n Jim\u00e9nez D\u00edaz Universidad Aut\u00f3noma de Madrid and Fundaci\u00f3n 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