Effects of captopril, telmisartan and bardoxolone methyl (CDDO‐Me) in ischemia‐reperfusion‐induced acute kidney injury in rats: an experimental comparative study

Abstract

Renal ischemia-reperfusion (IR) injury is one of the most common causes of acute kidney injury. This study investigated the effects of captopril (CAP), telmisartan (TEL) and bardoxolone methyl (BM) in animals with renal IR injury. Adult male Wistar-Albino rats were divided into six groups: control, vehicle, IR, IR with CAP, IR with TEL and IR with BM. Before IR was induced, drugs were administered by oral gavage. After a 60-min ischemia and a 120-min reperfusion period, bilateral nephrectomies were performed. Serum urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) levels, tissue total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), asymmetric dimethylarginine (ADMA) levels, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity were measured. Tissue mRNA expression levels of peroxisome proliferator-activated receptor-ɣ (PPAR-ɣ), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were analyzed. In addition, renal tissues were evaluated histopathologically and immunohistochemically. All tested drugs reduced renal damage, apoptosis, urea, creatinine, NGAL, TOS, nitric oxide (NO) and ADMA levels, NF-κB, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expressions (P < 0.001). All tested drugs increased SOD activity, GSH-Px activity, TAS levels, TT levels, endothelial nitric oxide synthase (eNOS) expression, dimethylarginine dimethylaminohydrolases (DDAHs) expression, Nrf2 expression and PPAR-ɣ expression (P < 0.001, P < 0.003). These results suggest that CAP, TEL and BM pretreatment could reduce renal IR injury via anti-inflammatory, antioxidant and anti-apoptotic effects.

Targeting oxidative stress, a crucial challenge in renal transplantation outcome

“…These results are confirmed in a rat model of I/R where pre-treatment few hours before injury with CDDO-methyl ester reduces early renal damage by reducing oxidative stress and increasing antioxidant defence (151). These studies demonstrate that CDDO derivatives have the potential to be used in clinic to reduce renal IR injury through antioxidant effects.…”

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

“…Alterations in the RAS have been shown to contribute to the development of AKI and are associated with adverse outcomes both in experimental and clinical studies [45][46][47][48][49][50]. Several components of the kidney RAS, such as urine Angiotensinogen and Ang II, the main active peptide, are increased in experimental AKI caused by ischemia-reperfusion AKI [45][46][47][51][52][53][54][55][56] ACE inhibitors (ACEi) and angiotensin receptor antagonists (ARBs) may attenuate renal inflammation, injury and improve renal function in the ischemia-reperfusion model of AKI [57][58][59][60]. Intrarenal Ang II is reportedly elevated in AKI, which may worsen kidney tissue injury independently of its hemodynamic effect that helps maintain renal circulation [61][62][63].…”

RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene

“…Nrf2, a cap'n'collar (CNC) basic-region leucine zipper (bZIP) transcription factor, influences intrinsic resistance to oxidative stress by inducing a battery of ROS-detoxifying enzymes and stimulates the production of antioxidants, including the tripeptide glutathione (GSH), thioredoxin (TXN), and sulfiredoxin (SRXN), all of which can reduce oxidized protein thiols [ 28 – 30 ]. A previous study demonstrated that the unbalanced redox state after IRI can be restored by the Nrf2 inducer and kidney injury can be alleviated by enhancing ROS detoxification [ 31 – 34 ]. These data suggest that the Nrf2 pathway is essential in protecting kidney against IRI.…”