Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat.

Catherine J Leader,Gerard T Wilkins,Ivan A Sammut,Robert J Walker,Darren J Kelly

doi:10.14814/phy2.14448

Catherine J Leader, Gerard T Wilkins + Show 3 more

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https://doi.org/10.14814/phy2.14448

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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.

Highlights

Hypertension is common in both developed and undeveloped countries (Kearney et al, 2005; Kearney, Whelton, Reynolds, Whelton, & He, 2004), and is considered a major risk factor for global morbidity and mortality (Benjamin et al, 2017; Lim et al, 2012)
Plasma creatinine was elevated over the 3 month experimental duration consistent with the development of chronic kidney disease (Table 1)
Severe hypertension in this Ren2 animal model over 12 weeks, resulting from upregulation of the renin angiotensin aldosterone axis, led to significant hypertensive nephrosclerosis with glomerulosclerosis and renal cortical interstitial fibrosis. This was associated with decreased kidney function and significant proteinuria

Summary

Introduction

Hypertension is common in both developed and undeveloped countries (Kearney et al, 2005; Kearney, Whelton, Reynolds, Whelton, & He, 2004), and is considered a major risk factor for global morbidity and mortality (Benjamin et al, 2017; Lim et al, 2012). A recently created model is the transgenic Cyp1a1Ren rat (Kantachuvesiri et al, 2001), in which hypertension can be reversibly induced by diet manipulation, to any desired level consistent with survival. In this transgenic rat, mouse Ren cDNA expression is under the control of an inducible cytochrome p450-1a1 promoter, integrated into the Y chromosome of Fischer 344 rats (Kantachuvesiri et al, 2001; Mitchell et al, 2006). Removal of I3C from the diet results in rapid restoration to pretreatment levels of blood pressure (Howard, Mullins, & Mitchell, 2010; Kantachuvesiri et al, 2001; Leader et al, 2018; Peters et al, 2012)

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