Abstract
ObjectivesThis study is to investigate whether the cardiac microvascular endothelial cells (CMECs) can regulate the autophagy of cardiomyocytes (CMs) by secreting lncRNA-ANRIL/miR-181b exosomes, thus participating in the occurrence of uremic cardiovascular disease (CVD).MethodsA 5/6 nephrectomy uremia model was established, with the mice injected with ANRIL-shRNA lentivirus vector, miR-181b agomir, and related control reagents, containing the serum creatinine and urea nitrogen measured. The renal tissue sections of mice were stained with Periodic Acid-Schiff (PAS), TUNEL, and Hematoxylin-Eosin (HE) performed on myocardial tissue sections of mice. ANRIL-shRNA, miR-181b mimics, and related control reagents were transfected into CMECs, in which the exosomes were extracted and co-cultured with CMs. The expressions of ANRIL, miR-181b and ATG5 were detected by qRT-PCR, and the expressions of autophagy related proteins by Western blot, as well as the binding of ANRIL and miR-181b by the double luciferase reporter gene experiment.ResultsANRIL down-regulation or miR-181b up-regulation can increase the weight of mice with uremia, as well as the expressions of p62 and miR-181b, and reduce the content of serum creatinine and urea nitrogen, the damage of kidney and myocardial tissues, the number of apoptotic cells in myocardial tissues, as well as the expressions of ANRIL, ATG5, Beclin1, and LC3. CMs can absorb the exosomes of CMECs. Compared with IS+ CMEC-Exo group, the expressions of ANRIL and ATG5 in CMs of IS+ CMEC-Exo + sh lncRNA ANRIL and IS+CMEC-Exo+miR-181b mimics groups was down-regulated, as well as the expressions of ATG5, Beclin1, and LC3, while miR-181b expression was up-regulated as well as P62 expression.ConclusionsCMECs can regulate autophagy of CMs by releasing exosomes containing ANRIL and miR-181b.
Highlights
Chronic kidney disease (CKD) has become a global public health problem with high morbidity and mortality, among which cardiovascular disease (CVD) is the main cause of death [1]
ANRIL down-regulation or miR-181b up-regulation can increase the weight of mice with uremia, as well as the expressions of p62 and miR-181b, and reduce the content of serum creatinine and urea nitrogen, the damage of kidney and myocardial tissues, the number of apoptotic cells in myocardial tissues, as well as the expressions of ANRIL, ATG5, Beclin1, and LC3
In diabetic cardiomyopathy (DCM), exosomes derived from cardiac microvascular endothelial cells (CMECs) can be absorbed by CMs, to increase the content of Mst1 protein in CMs, inhibiting the autophagy of high glucose (HG) cells (25mmol/l) and promoting the apoptosis [3]
Summary
Chronic kidney disease (CKD) has become a global public health problem with high morbidity and mortality, among which cardiovascular disease (CVD) is the main cause of death [1]. As an essential regulatory RNA molecule, lncRNAs have been reported to be involved in the occurrence of renal inflammation in kidney-related diseases [2], which are becoming a potential key regulator in various CVDs at the same time. It is still unclear whether lncRNAs are involved in the pathogenesis of uremic cardiomyopathy, with the in-depth molecular regulatory mechanism to be explored. More and more studies have shown that exosomes containing secreting factors of CMECs can effectively regulate cardiac functions and positively or negatively affect cardiac remodeling [4], suggesting that in uremia cardiomyopathy, lncRNAs encapsulated in exosomes may regulate the autophagy and apoptosis of CMs through CMECs and CM corsstalk, regulating the occurrence and development of the disease
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