Background-The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B 1 -and B 2 -receptor expression, which are the molecular entities responsible for the biological effects of kinins. Methods and Results-Rats were subjected to different 6-week treatments using various mixtures of the following agents:ACE inhibitor, angiotensin AT 1 -receptor antagonist, and B 1 -and B 2 -receptor antagonists. Chronic ACE inhibition induced both renal and vascular B 1 -receptor expression, whereas B 2 -receptor expression was not modified. Furthermore, with B 1 -receptor antagonists, it was shown that B 1 -receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B 1 -receptors in all segments. ACE-inhibitor-induced B 1 -receptor induction involved homologous upregulation, because it was prevented by B 1 -receptor antagonist treatment. Finally, using B 2 -receptor knockout mice, we showed that ACE-inhibitor-induced B 1 -receptor expression was B 2 -receptor independent. Conclusions-This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B 1 -receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B 1 -receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.
Chaabane W, Praddaude F, Buleon M, Jaafar A, Vallet M, Rischmann P, Galarreta CI, Chevalier RL, Tack I. Renal functional decline and glomerulotubular injury are arrested but not restored by release of unilateral ureteral obstruction (UUO). Am J Physiol Renal Physiol 304: F432-F439, 2013. First published December 5, 2012; doi:10.1152/ajprenal.00425.2012.-Murine unilateral ureteral obstruction (UUO), a major model of progressive kidney disease, causes loss of proximal tubular mass and formation of atubular glomeruli. Adult C57BL/6 mice underwent a sham operation or reversible UUO under anesthesia. In group 1, kidneys were harvested after 7 days. In group 2, the obstruction was released after 7 days, and a physiological study of both kidneys was performed 30 days later. Renal blood flow (RBF), glomerular filtration rate (GFR), urine protein, and albumin excretion were measured after ligation of either the left or right ureter. Glomerular volume (periodic acidSchiff), glomerulotubular integrity and proximal tubular mass (Lotus tetragonolobus lectin), and interstitial collagen (Sirius red) were measured by histomorphometry. Obstructed kidney weight was reduced by 15% at 7 days but was not different from sham after a 30-day recovery. Glomerular volume and proximal tubular area of the obstructed kidney were reduced by 55% at 7 days, but normalized after 30 days. Interstitial collagen deposition increased 2.4-fold after 7 days of UUO and normalized after release. However, GFR and RBF were reduced by 40% and urine albumin/protein ratio was increased 2.8-fold 30 days after release of UUO. This was associated with a 50% reduction in glomerulotubular integrity despite a 30-day recovery (P Ͻ 0.05 for all data). We conclude that release of 7-day UUO can arrest progression but does not restore normal function of the postobstructed kidney. Although the remaining intact nephrons have hypertrophied, glomerular injury is revealed by albuminuria. These results suggest that glomerulotubular injury should become the primary target of slowing progressive kidney disease. glomerular filtration rate; albuminuria; renal hypertrophy; atubular glomeruli; proximal tubule; fibrosis PARENCHYMAL LOSS AND PROGRESSIVE interstitial fibrosis are common features of chronic kidney disease (23). Unilateral ureteral obstruction (UUO) is the animal model most widely used to study the development of tissue damage and fibrosis. In addition, release of obstruction permits examination of renal repair (for a review, see Ref. 5). The renal impact of UUO varies with animal species, and until the past decade rabbits, dogs, and rats have been mostly used (21). However, most studies are currently performed in mice, which offer a variety of genetically engineered animals (9, 12, 16). Because of its technical difficulty, the use of reversible models of UUO in mice remains limited and little information is available regarding the renal functional impact of UUO and its relief. As in humans, most species exhibit a compensatory renal growth of the nonobstructed kidney ...
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