Artikel
Blood Pressure and direct Mineralocorticoid Effects mediate Glomerular Inflammation and Injury in Hypertension
Blutdruck und direkte Mineralkortikoid-Effekte vermitteln glomeruläre Entzündung und Schädigung bei Hypertonie
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Veröffentlicht: | 10. August 2005 |
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Objectives: We examined the contribution of high blood pressure per se versus direct effects of the mineralocorticoid to kidney injury and inflammation in experimental DOCA-salt hypertension.
Design and methods: Male uninephrectomized Sprague-Dawley rats received 1% NaCl for drinking and DOCA pellets (100 mg over 6 weeks) subcutaneously, or were sham operated. After 4 weeks, rats were treated with a non-hypotensive dose of spironolactone (SPL, 100 mg/kg, daily gavage, n=7), or triple therapy (TRP, hydrochlorithiazide, reserpine and hydralazine, n=8) dosed to normalize blood pressure, or with vehicle (n=14) for the final two weeks. Mean blood pressure was measured intraarterially in conscious rats. In kidney sections, macrophage infiltration, glomerulosclerosis and interstitial fibrosis were evaluated.
Results: Mean blood pressure was elevated in vehicle-treated DOCA rats (174±9 versus 115±4 mmHg in normotensive rats, p<0.01), not affected by SPL (168±8 mmHg), and almost normalized by TRP (125±7 mmHg, p<0.05 vs. DOCA). Parallel changes of relative left ventricular weight were observed. Urinary protein excretion was grossly elevated in vehicle-treated DOCA rats, tended to be somewhat lower in SPL treated rats, and was markedly decreased by TRP. In contrast, glomerular infiltration of macrophages in DOCA rats (4.2±0.5 versus 0.9±0.1 macrophages per glomerular cross-section in normotensive controls, p<0.01) was more reduced by SPL (1.5±0.2, p<0.05) than by TRP (2.1±0.3). DOCA rats developed marked glomerulosclerosis and interstitial fibrosis which was alleviated by SPL and TRP to a similar extent.
Conclusions: In the DOCA-salt model of nephrosclerosis, direct mineralocorticoid effects contribute importantly to the infiltration of macrophages. Both high blood pressure and mineralocorticoid effects contribute independently, and to a similar extent, to the development of glomerulosclerosis and interstitial fibrosis.