Ischemic preconditioning protects the heart against ischemia-reperfusion injury in chronic kidney disease in both males and females

Abstract

Background Uremic cardiomyopathy is a common cardiovascular complication of chronic kidney disease (CKD) characterized by left ventricular hypertrophy (LVH) and fibrosis enhancing the susceptibility of the heart to acute myocardial infarction. In the early stages of CKD, approximately 60% of patients are women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning (IPRE) in experimental CKD. Methods CKD was induced by 5/6 nephrectomy in 9-week-old male and female Wistar rats. Two months later, serum and urine laboratory parameters were measured to verify the development of CKD. Transthoracic echocardiography was performed to assess cardiac function and morphology. Cardiomyocyte hypertrophy and fibrosis were measured by histology. Left ventricular expression of A- and B-type natriuretic peptides (ANP and BNP) were measured by qRT-PCR and circulating BNP level was measured by ELISA. In a subgroup of animals, hearts were perfused according to Langendorff and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPRE (3 × 5 min I/R cycles applied before index ischemia). Then infarct size or phosphorylated and total forms of proteins related to the cardioprotective RISK (AKT, ERK1,2) and SAFE (STAT3) pathways were measured by Western blot. Results The severity of CKD was similar in males and females. However, CKD males developed more severe LVH compared to females as assessed by echocardiography. Histology revealed cardiac fibrosis only in males in CKD. LV ANP expression was significantly increased due to CKD in both sexes, however, LV BNP and circulating BNP levels failed to significantly increase in CKD. In both sexes, IPRE significantly decreased the infarct size in both the sham-operated and CKD groups. IPRE significantly increased the phospho-STAT3/STAT3 ratio in sham-operated but not in CKD animals in both sexes. There were no significant differences in phospho-AKT/AKT and phospho-ERK1,2/ERK1,2 ratios between the groups. Conclusion The infarct size-limiting effect of IPRE was preserved in both sexes in CKD despite the more severe uremic cardiomyopathy in male CKD rats. Further research is needed to identify crucial molecular mechanisms in the cardioprotective effect of IPRE in CKD.

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

“…Cardiac morphology and function were assessed by transthoracic echocardiography as described previously [ 59 , 60 ], at weeks 1, 3, and 15 to monitor the development of RIHD. Rats were anesthetized with 2% isoflurane (Forane, Aesica, Queenborough Limited, Queenborough, UK).…”

“…Quantitative RT-PCR was performed with gene-specific primers to monitor mRNA expression as described previously [ 59 , 60 ]. RNA was isolated using Qiagen RNeasy Fibrous Tissue Mini Kit (Qiagen, Hilden, Germany) from heart tissue.…”

“…To investigate gene expression changes at the protein level, a standard Western blot technique was used as described previously [ 59 , 60 ]. AT1R (41 kDa), AT2R (41 kDa), SMAD2/3 (52 and 60 kDa), TGF-βRII (85 kDa), STAT3 (79 and 86 kDa), pSTAT3 (79 and 86 kDa), AKT (60 kDa), pAKT (60 kDa), ERK1/2 (42 and 44 kDa), and pERK1/2 (42 and 44 kDa) with GAPDH (37 kDa) loading background were assessed at weeks 1, 3, and 15.…”

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

“…In both sexes, however, ischemic PreC decreased IS in sham and CKD animals. Interestingly, ischemic PreC increased the phospho-STAT3/STAT3 ratio in sham-operated but not CKD animals in both sexes, while no differences in phospho-AKT/AKT and phospho-ERK/ERK ratios existed ( Sárközy et al, 2021 ). Thus, the underlying signaling events might differ between sham (SAFE-pathway-dependent) and CKD animals (SAFE- and RISK-pathway independent).…”

Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model

“…Serum carbamide and creatinine levels were quantified by kinetic UV method using urease and glutamate dehydrogenase enzymes and Jaffe method, respectively. All reagents and instruments for the serum parameter measurements were from Roche Diagnostics (Hoffmann-La Roche Ltd., Basel, Switzerland), as described previously [76]. Cardiovascular risk factors, including serum cholesterol and triglyceride levels, were also measured by Roche Cobas 8000 analyzer system using enzymatic colorimetric assays from Roche (Hoffmann-La Roche Ltd., Basel, Switzerland) [29].…”