Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging.

Basma Ismail,Tayebeh Hadizad,Kevin D Burns,Rob S Beanlands,Etienne Croteau,Rob A Dekemp,Jean N Dasilva,Jaap A Joles

doi:10.1371/journal.pone.0177451

Basma Ismail, Tayebeh Hadizad + Show 6 more

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https://doi.org/10.1371/journal.pone.0177451

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Abstract

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8–10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18–20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

Highlights

IntroductionChronic kidney disease (CKD) is a growing health problem worldwide with increasing annual incidence at a rate of 8%, and consumes up to 2% of the global health expenditure [1]
renin angiotensin (Ang) system (RAS) blockade with Ang-converting enzyme inhibitors (ACEIs) or AT1 receptor (AT1R) blockers (ARBs) have been shown in landmark clinical trials to dramatically attenuate the decline in renal function associated with Chronic kidney disease (CKD) [12,13,14,15,16]
The major finding is the in vivo demonstration of renal AT1R reduction associated with the activated RAS due to CKD-induced hypertension in Nx rats, which was normalized following administration of the ACEI enalapril

Summary

Introduction

Chronic kidney disease (CKD) is a growing health problem worldwide with increasing annual incidence at a rate of 8%, and consumes up to 2% of the global health expenditure [1]. RAS blockade with Ang-converting enzyme inhibitors (ACEIs) or AT1 receptor (AT1R) blockers (ARBs) have been shown in landmark clinical trials to dramatically attenuate the decline in renal function associated with CKD [12,13,14,15,16]. Alternative antihypertensive drugs given alone or in combination were shown to be successful in reaching optimal blood pressure target and in slowing progression of CKD. In this regard, calcium channel blockers (CCBs) are as efficient as RAS blockers at attenuating hypertension-related renal damage progression, when administered during the non-proteinuric stages of CKD [17,18,19,20,21]. The use of dihydropyridine and nondihydropyridine CCBs has been reported to be safe and effective in management of CKD, provided that a tight control of blood pressure was achieved (reviewed in [22,23,24,25])

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