Decreased renal AT(1) receptor binding in rats after subtotal nephrectomy: PET study with [(18)F]FPyKYNE-losartan

BACKGROUND: 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). Numerous studies have provided evidence for the role of angiotensin (Ang) II type 1 receptor (AT(1)R) in the promotion and progression of the disease; however, conflicting results were reported on intrarenal AT(1)R levels in CKD models. METHODS: Male Sprague-Dawley rats (n = 26) underwent Nx or sham operations. Animals were scanned at 8–10 weeks post-surgery with PET using the novel AT(1)R radioligand [(18)F]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 (125)I-[Sar(1), Ile(8)]Ang II autoradiography were performed to assess AT(1)R expression. RESULTS: At 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. CONCLUSIONS: Reduced renal AT(1)Rs in hypertensive rats measured with [(18)F]FPyKYNE-losartan PET at 8–10 weeks following Nx support further use of this non-invasive approach in longitudinal studies to better understand the AT(1)R role in CKD progression.