The effect of neprilysin and renin inhibition on the renal dysfunction following ischemia-reperfusion injury in the rat

The natriuretic peptide (NP) system counter-regulates the renin-angiotensin system (RAS), so enhancing the activity of natriuretic peptides (NPs) may be beneficial in conditions when RAS is activated such as ischemia-reperfusion injury (IRI). Neprilysin is the key enzyme responsible for the degradation of NPs. The effects of neprilysin inhibition or the combination of neprilysin inhibition and RAS inhibition on renal IRI-induced renal dysfunction have not been investigated yet. To investigate this, rats underwent sham surgery or bilateral IRI for 20 min. G-Als, G-Scb, and G-Als+Scb underwent similar protocol but received aliskiren (renin inhibitor), sacubitril (neprilysin inhibitor) or a combination of both pre- and post-IRI, respectively. IRI caused significant alterations in all renal functional parameters, markers of acute renal injury, pro-inflammatory and pro-fibrotic cytokines, and histological features. All these alterations were significantly attenuated in G-Als, G-Scb, and G-Als+Scb. The attenuations in the alterations in serum creatinine, creatinine clearance, and histological features were larger in G-Als+Scb compared to either G-Als or G-Scb. We conclude that RAS blockade by a renin inhibitor (aliskiren) or neprilysin inhibition by sacubitril separately led to significant attenuation in the renal IRI-induced renal dysfunction. The combination of aliskiren and sacubitril was more effective than either one alone.