Angiotensin Receptor Neprilysin Inhibition mediates Renal Protection by ARNI (Sacubatril Valsartan) in Rats with Spontaneous Hypertension

Background This article aims to present research pertaining to the effect of angiotensin receptor-neprilysin double blocker on blocking the inflammatory mechanism mediated by NLRP3 inflammasome on hypertensive nephropathy. ARNI has not only been found to improve cardiac function but is also associated with a reduction in progressive deterioration of kidney function owing to hypertension by exerting anti-inflammation, anti-autophagy, anti-fibrosis and anti-Golgi’s apparatus. We hypothesized that administration of ARNI is more effective than valsartan alone in slowing progression of hypertensive renal disease. Methods Rat models with spontaneous hypertension were randomized into a no treatment group, valsartan group (60 mg/kg), ARNI group (70 mg/kg) or ARNI + A779 group (70 mg/kg + 400ng/kg) daily by gavage. Sprague-Dawley rats were subjected to the control conditions (without hypertension and treatment). The kidney tissue analyses were performed after 12 weeks. We detected the expression levels of NLRP3 and casepase-1 in kidney tissue, and NLRP3 levels in human embryonic kidney cells which were induced by ang II as hypertension cell model by Real-Time Polymerase Chain Reaction. To analyze the impact of ARNI on autophagy, we performed western blot analysis on renal tubules to measure the protein expression of NLRP3 inflammasome, and to measure the protein expression of P62 and LC3. Masson 3 staining method was used to stain renal fibrosis. Immunohistochemistry was performed to determine the expression sites of NLRP3. The Golgi apparatus in morphology of renal tubular cells was determined by transmission electron microscope. Results The untreated hypertensive renal disease rats exhibited tubular and glomerular damage, downregulation of pro-inflammatory, pro-autophagy, pro-fibrotic and pro-Golgi’s apparatus pathways. ARNI administration improved renal function and histology changes and attenuated most of the molecular markers of inflammation, autophagy, fibrosis and Golgi’s apparatus. Conclusions ARNI activation attenuates renal complications of arterial hypertension by reduction of kidney inflammation through selective actions requiring the renal tubular epithelium but not the glomerular endothelial cells and the circumferential mesangial interposition cell Angiotensin Receptor. ARNI was more effective than valsartan therapy alone in delaying the progression of hypertensive renal disease.