| ROLE OF THE RENIN-ANGIOTENSIN SYSTEM DURING KIDNEY DEVELOPMENT | |
| Research field: | Kidney physiology |
| Authors: | P. Friberg, G. Guron, A. Nilsson, Y. Chen, D.Lasaitiene, P. Hansell, N. Marcussen |
| Address of presenting author: | Dept of Clinical Physiology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden |
| E-mail: | fribergp@mednet.gu.se |
| Phone: | +46 31 342 1596 |
| Fax: | +46 31 827614 |
| Text of abstract |
Introduction Our results have demonstrated that pharmacological blockade of the renin-angiotensin system (RAS) in neonatal rats with immature kidneys caused persistent renal morphological abnormalities. These involve papillary atrophy, tubulo-interstital inflammation and fibrosis, tubular atrophy and dilatation and wall thickening of interlobular arteries. Adult rats exposed to neonatal RAS interruption showed a modest (15%) reduction in glomerular filtration rate and a substantial impairment in urinary concentrating ability of renal origin. During dietary sodium loading these rats showed evidence for sodium retention, possibly caused by inadequate generation of renal interstitial hydrostatic pressure. Angiotensin II is essential for developing a normal structural integrity of the renal inner medulla. AngII may, besides its own growth promotion features, also stimulate other growth factors. Niimura et al found a downregulation of PDGF-A gene transcription in the atrophied papilla of 3-week-old Agt-/- mice and recent experiments in our laboratory have demonstrated that enalapril treatment in the neonatal rat produces a reduction in IGF-1 mRNA levels confined specifically to the renal medulla. Indeed, exogenous administration of recombinant IGF-1 markedly attenuated the development of papillary lesions and restored completely urinary concentrating ability. Moreover, recent data in newborn rats treated with enalapril have shown increased activities of Caspase 1, 3 and 6 in the renal medulla, suggesting that an enhanced caspase-dependent apoptosis may contribute to the development of papillary atrophy. One may also consider that renal medullary hypoperfusion with resultant renal ischemia would also be involved in the development of papillary atrophy. This appears, however, not to be the case, since even lower deep medullary oxygen tension was produced with drugs that did not cause renal abnormalities. Recent experiments have clearly demonstrated increased levels of intrarenal hyaluronic acid in rats subjected to neonatal enalapril treatment. It is tempting to speculate that this glycosaminoglycan may be involved in the initiation of the wide-spread interstitial inflammation and fibrosis observed in this renal damage model. We have also noted the appearance of macrophage infiltration after about 7 to 9 days of enalapril treatment and T-cell accumulation somewhat later. These studies show the salient role of the RAS in normal kidney development. Although the specific role for angiotensin II in renal development has to be unravelled, our recent experiments indicate that IGF-1 is involved, since it appears to be modulated by the RAS particularly with regard to the inner medulla. Further, the recent demonstration of reduced medullary aquaporin-2 (water-permeable protein), the increased levels of hyaluronic acid, the interstitial inflammation together with the pronounced papillary atrophy will hamper water reabsorption, thereby disturbing the propensity for adequately concentrating the urine.
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| Keywords: | kidney, renin, blood pressure, nephrogenesis |
Created 2000-04-28