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

ABSTRACT: 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.

SUBMITTER: Hammad FT

PROVIDER: S-EPMC7957268 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Hammad Fayez T FT Al-Salam Suhail S AlZaabi Sarah S SS Alfalasi Maryam M MM Hammad Awwab F AF Yasin Javed J Lubbad Loay L

Physiological reports 20210301 6

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 th ...[more]

PMID: 33719192

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Project description:BackgroundRenal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI.MethodsMale Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1-72 h reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.ResultsTreprostinil significantly reduced peak elevated serum creatinine (SCr) levels and accelerated normalization relative to IRI-placebo (p < 0.0001). Treatment with treprostinil also inhibited IRI-mediated renal apoptosis, mitochondrial oxidative injury (p < 0.05), and the release of cytochrome c (p < 0.01) vs. IRI-placebo. In addition, treprostinil preserved renal mitochondrial DNA copy number (p < 0.0001) and renal ATP levels (p < 0.05) to nearly those of sham-operated animals. Non-targeted semi-quantitative proteomics showed reduced levels of ATP synthase subunits in the IRI-placebo group which were restored to sham levels by treprostinil treatment (p < 0.05). Furthermore, treprostinil reduced renal IRI-induced upregulated Drp1 and pErk protein levels, and restored Sirt3 and Pgc-1α levels to baseline (p < 0.05).ConclusionsTreprostinil reduces mitochondrial-mediated renal apoptosis, inhibits mitochondria fission, and promotes mitochondria fusion, thereby accelerating mitochondrial recovery and protecting renal proximal tubules from renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI.

Dataset Information

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

Publications

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

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