Abstract
BackgroundSignificant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) is associated with a chain of events that culminates in hypertension and chronic kidney disease (CKD). Numerous studies have provided evidence for the role of angiotensin (Ang) II type 1 receptor (AT1R) in the promotion and progression of the disease; however, conflicting results were reported on intrarenal AT1R levels in CKD models.MethodsMale Sprague-Dawley rats (n = 26) underwent Nx or sham operations. Animals were scanned at 8–10 weeks post-surgery with PET using the novel AT1R radioligand [18F]FPyKYNE-losartan. Radioligand binding was quantified by kidney-to-blood ratio (KBR), standard uptake value (SUV), and distribution volume (DV). After sacrifice, plasma and kidney Ang II levels were measured. Western blot and 125I-[Sar1, Ile8]Ang II autoradiography were performed to assess AT1R expression.ResultsAt 8–10 weeks post-surgery, Nx rats developed hypertension, elevated plasma creatinine levels, left ventricle hypertrophy, increased myocardial blood flow (MBF), and reduced Ang II levels compared to shams. PET measurements displayed significant decrease in KBR (29 %), SUV (24 %), and DV (22 %) induced by Nx (p < 0.05), and these findings were confirmed by in vitro assays.ConclusionsReduced renal AT1Rs in hypertensive rats measured with [18F]FPyKYNE-losartan PET at 8–10 weeks following Nx support further use of this non-invasive approach in longitudinal studies to better understand the AT1R role in CKD progression.
Highlights
Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) is associated with a chain of events that culminates in hypertension and chronic kidney disease (CKD)
At baseline, measured left ventricle (LV) mass and %ejection fraction (EF) were comparable between groups
LV %EF was not affected in 5/6 nephrectomy (Nx) rats, whereas a significant increase in LV mass was detected at 8–10 weeks post-surgery (1201 ± 215 vs 874.4 ± 117, respectively, p < 0.002)
Summary
Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) is associated with a chain of events that culminates in hypertension and chronic kidney disease (CKD). Significant renal mass reduction induced by subtotal 5/6 nephrectomy (Nx) is a model of chronic kidney disease (CKD), which involves deterioration of renal function due to loss of substantial number of nephrons and compensatory hypertrophy in the remnant kidney. In this model, the development of hypertension, proteinuria, and progressive renal fibrosis eventually leads to end-stage renal disease [1,2,3]. The AT1AR represents the homologous form of the human AT1R and is widely distributed on luminal membranes throughout the nephron segments [18]
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