title: Angiotensin II-AT1-receptor signaling is necessary for cyclooxygenase-2-dependent postnatal nephron generation.
abstract: Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2-dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2-/-mice was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P3 to P8, the critical time frame of renal COX-2 expression, led to hypoplastic glomeruli, a thinned subcapsular cortex and maturational arrest of superficial glomeruli quite similar to that observed in COX-2-/-mice. In contrast, AT2 receptor antagonist PD123319 was without any effect on renal development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2-/-pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L162313 rescued impaired renal function by reducing serum urea and creatinine and mitigated pathologic albumin excretion. Moreover, glomerulosclerosis in the kidneys of COX-2-/-mice was reduced. Thus, angiotensin II-AT1-receptor signaling is necessary for COX-2-dependent normal postnatal nephrogenesis and maturation.
authors.affiliation: Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Frölich
authors.affiliation: Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Slattery
authors.affiliation: Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Institute of Pharmacology and Toxicology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.affiliation: Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.affiliation: Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany. Electronic address: r.m.nuesing@med.uni-frankfurt.de.
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
mesh_terms: D000367:Age Factors; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D003404:Creatinine / Q000097:blood; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000378:metabolism; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014508:Urea / Q000097:blood
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D014508:Urea; D003404:Creatinine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D012083:Renin; D015232:Dinoprostone
keywords: cyclooxygenase; nephrogenesis; prostaglandin; renin angiotensin system