title: Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model.
abstract: Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1-3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor β (Pdgfrb). Treatment of ischemic mice with the x03B3;-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis.
authors.affiliation: Department of Virology and Cell Biology, University of Lx00FC;beck, Lx00FC;beck, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kramer
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwanbeck
authors.forename: Horst
authors.initials: H
authors.lastname: Pagel
authors.forename: Figen
authors.initials: F
authors.lastname: Cakiroglu
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohwedel
authors.forename: Ursula
authors.initials: U
authors.lastname: Just
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D020797:Receptor, Platelet-Derived Growth Factor beta; D053829:Amyloid Precursor Protein Secretases