Angiotensin II-AT1–receptor signaling is necessary for cyclooxygenase-2–dependent postnatal nephron generation

Stefanie Frölich, Patrick Slattery, Dominique Thomas, Itamar Goren, Nerea Ferreiros, Boye L. Jensen, Rolf M Nüsing

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalKidney International
Volume91
Issue number4
Pages (from-to)818-829
ISSN0085-2538
DOIs
Publication statusPublished - 2017

Keywords

  • cyclooxygenase
  • nephrogenesis
  • prostaglandin
  • renin angiotensin system

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