Angiotensin II-mediated improvement of renal mitochondrial function via the AMPK/PGC-1α/NRF-2 pathway is superior to norepinephrine in a rat model of septic shock associated with acute renal injury

Abstract

Background: This study sought to compare the therapeutic effects of angiotensin II (ANG II) and norepinephrine (NE) on cecal ligation and puncture (CLP)-induced septic acute kidney injury (AKI) in rats.Methods: Sepsis shock was induced in anesthesia Sprague-Dawley male rats by CLP model for 24 hours.A total of 40 rats were divided into five groups, including control group, sham group, CLP group, CLP + ANG II group, and CLP + NE group. CLP + ANG II and CLP + NE group were administration of ANG II or NE after sepsis shock respectively, maintaining the MAP at 75-85 mmHg. CLP group was administration of saline for contrast. At 0, 18, 24 hours measured the renal blood grades and resistant index (RI) by ultrasound equipment. At 6, 12, 18 and 24 hours collected 0.5 mL blood sample for creatinine and lactic acid examination. Rats were observed for 24 hours after CLP procedure and then sacrificed for subsequent examination, rat serum were used to determine the levels of inflammatory response factors, kidney tissues were used to examine the oxidative stress factors and mitochondrial related proteins." We added the sentence as following: "The AMPK, PGC-1α and NRF-2 expression in renal cortex was significantly increased in the CLP + ANG Ⅱ group.Results: Compared to the vehicle treatment, both ANG II and NE administration restored the decrease in the mean arterial pressure (MAP) and alleviated mitochondrial impairments in CLP rats. However, only ANG II alleviated CLP-induced abnormalities in serum creatinine and lactic acid concentrations, renal blood flow, the renal resistant index, renal histopathology, the production of proinflammatory cytokines, and oxidative stress markers in rats. ANG II was also found to be superior to NE in reversing the CLP-induced suppression of mitochondrial biogenesis-related protein expression in the kidneys of rats.Conclusions: ANG II was better than NE in alleviating CLP-induced septic AKI in rats.

The Effects of a Meldonium Pre-Treatment on the Course of the Faecal-Induced Sepsis in Rats

“…Our results showed that neither meldonium nor treatments significantly altered PGC1-α protein level in any of the examined tissues ( Figure 5 ), in contrast to studies on different models of sepsis showing a reduction of PGC1-α content in the heart, kidney, and liver [ 76 , 77 , 78 , 79 ]. Since the proposed mechanism of PGC1-α downregulation under the septic conditions includes NF-kB activation [ 80 , 81 ], which we did observe, the supposed inconsistency between our results and those previously published could be explained by the difference in the experimental designs.…”

“…Since the proposed mechanism of PGC1-α downregulation under the septic conditions includes NF-kB activation [ 80 , 81 ], which we did observe, the supposed inconsistency between our results and those previously published could be explained by the difference in the experimental designs. Specifically, the experimental design mentioned in the literature implied tissue collection 12–72 h following the sepsis induction [ 76 , 77 , 78 , 79 ]. In contrast, we collected organs as early as within 8–9 h due to the high mortality rate following FIP injection.…”

Targeting the AMPK/Nrf2 Pathway: A Novel Therapeutic Approach for Acute Lung Injury

“…AMPK, an upstream enzyme of Nrf2, enhances the expression of antioxidant genes, thereby inhibiting oxidative damage. 79 Additionally, AMPK can trigger the phosphorylation of residue Ser558 (Ser550 in mice) on Nrf2, influencing the nuclear accumulation of Nrf2. 80 Notably, following the mutation of this residue, the activation of AMPK is unable to promote the nuclear import of Nrf2.…”