The renin-angiotensin system in kidney development: role of COX-2 and adrenal steroids.
Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay significantly elevated in the suckling period while aldosterone stabilizes at an adult level. COX-2 is stimulated in thick ascending limb of Henle's loop in the suckling period at a time when urine concentrating ability is not developed. Data suggest that this induction is mediated by combined low plasma glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX-2 and COX-2 null mice show that COX-2 activity stimulates renin secretion from JG-cells during postnatal kidney development and that lack of COX-2 activity leads to pathological change in cortical architecture and eventually to renal failure. In the postnatal period, ANG II initiates and maintains pelvic and ureteric contractions necessary for urine flow. Lack of ANG II in the neonatal period is thought to cause injury by a chronic increase of renal pelvic pressure. Aldosterone is crucial for survival and growth in the neonatal period through its effects on sodium reabsorption and the intrarenal sensitivity to aldosterone is increased in the postnatal period. Final maturation of the kidney occurs through an intimate interplay between a low dietary sodium intake and a non-responsive HPA-axis which stimulates cortical COX-2 activity. COX-2 supports increased activity of the RAAS and may contribute to a low concentrating ability.
Department of Physiology and Pharmacology, Institute of Medical Biology, University of Southern Denmark, Denmark.
B L
BL
Jensen
J
J
Stubbe
K
K
Madsen
F T
FT
Nielsen
O
O
Skøtt
D000818:Animals; D051546:Cyclooxygenase 2; D005314:Embryonic and Fetal Development / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology*; D007668:Kidney / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D012083:Renin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*
D007527:Isoenzymes; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin