Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat
Abstract Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate...
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doaj-7b538cbd83e446bca62cbd2a518b13c52020-11-25T02:50:36ZengWileyPhysiological Reports2051-817X2020-05-01810n/an/a10.14814/phy2.14448Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive ratCatherine J. Leader0Darren J. Kelly1Ivan A. Sammut2Gerard T. Wilkins3Robert J. Walker4Department of Medicine University of Otago Dunedin New ZealandDepartment of Medicine University of Melbourne Melbourne VIC AustraliaDepartment of Pharmacology University of Otago Dunedin New ZealandDepartment of Medicine University of Otago Dunedin New ZealandDepartment of Medicine University of Otago Dunedin New ZealandAbstract Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole‐3‐carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis.https://doi.org/10.14814/phy2.14448fibrosishypertensionkidneyspironolactone |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Catherine J. Leader Darren J. Kelly Ivan A. Sammut Gerard T. Wilkins Robert J. Walker |
spellingShingle |
Catherine J. Leader Darren J. Kelly Ivan A. Sammut Gerard T. Wilkins Robert J. Walker Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat Physiological Reports fibrosis hypertension kidney spironolactone |
author_facet |
Catherine J. Leader Darren J. Kelly Ivan A. Sammut Gerard T. Wilkins Robert J. Walker |
author_sort |
Catherine J. Leader |
title |
Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat |
title_short |
Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat |
title_full |
Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat |
title_fullStr |
Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat |
title_full_unstemmed |
Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat |
title_sort |
spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat |
publisher |
Wiley |
series |
Physiological Reports |
issn |
2051-817X |
publishDate |
2020-05-01 |
description |
Abstract Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole‐3‐carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis. |
topic |
fibrosis hypertension kidney spironolactone |
url |
https://doi.org/10.14814/phy2.14448 |
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