Increased myocardial ischemia-reperfusion injury in renal failure involves cardiac adiponectin signal deficiency

Abstract

Tao L. Increased myocardial ischemiareperfusion injury in renal failure involves cardiac adiponectin signal deficiency. Am J Physiol Endocrinol Metab 306: E1055-E1064, 2014. First published March 4, 2014 doi:10.1152/ajpendo.00428.2013.-Plasma levels of adiponectin (APN) are significantly increased in patients with renal dysfunction and are inversely related to the risk of cardiovascular mortality. The present study was designed to determine the role of APN in myocardial ischemia-reperfusion (MI/R) injury in mice with renal failure and delineate the underlying mechanisms. Renal failure was induced by subtotal nephrectomy (SN). Human recombinant globular domain of adiponectin (gAd) or full-length adiponectin (fAd) was administered via intraperitoneal injection once daily for 7 consecutive days after SN, and in vivo MI/R was introduced 3 wk later. Both plasma and urinary levels of APN increased significantly in SN mice. Compared with sham-operated mice, cardiac function was significantly depressed, and myocardial infarct size and apoptosis increased in SN mice following MI/R. The aggravated MI/R injury was further intensified in APN-knockout mice and markedly ameliorated by treatment with gAd but not fAd. Moreover, SN increased myocardial NO metabolites, superoxide, and their cytotoxic reaction product peroxynitrite, upregulated inducible NO synthase expression, and decreased endothelial NOS phosphorylation. In addition, SN mice also exhibited reduced APN receptor-1 (AdipoR1) expression and AMPK activation. All these changes were further amplified in the absence of APN but reversed by gAd treatment. The present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic-reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the protective role of exogenous supplement of gAd on MI/R outcomes in renal failure. adiponectin; renal failure; subtotal nephrectomy; oxidative/nitrative stress CHRONIC KIDNEY DISEASE (CKD) is a major public health problem worldwide that has been repeatedly documented to be associated with increased risk for cardiovascular morbidity and mortality. It has been increasingly apparent that accelerated cardiovascular disease is prevalent in individuals with CKD and has become the leading complication of renal insufficiency. In particular, the incidence of acute myocardial infarction among patients with CKD is more than twice that of patients without CKD (28). Therefore, the prevention and treatment of cardiac insult are critical considerations in the management of individuals with CKD. Adiponectin (APN), a 30-kDa adipocyte-derived vasoactive peptide involved in the regulation of inflammation and energy metabolism, has shown beneficial effects on cardiovascular disorders (11). It is highly abundant in the circulation and exists as trimers, hexamers, or high-molecular-weight multimers (22). Hypoadiponenemia has been observed in individuals with i...

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease

“…Thus, although a rat with 5/6 nephrectomy is an established model of CKD [3,8,12,35], impaired Aktmediated signaling upon reperfusion shown by the present study is unlikely to be the only mechanism of increased myocardial susceptibility to ischemia/reperfusion in CKD. In fact, mitochondrial dysfunction [36] and down-regulated expression of the adiponectin receptor in the myocardium [35] were reported to be associated with increased myocardial injury by CKD. In our study conducted in parallel with this study [26], disturbed malate-aspartate shuttle in the myocardium in CKD was indicated by results of metabolome analysis.…”

Leptin and Adiponectin During the First Week After Kidney Transplantation: Biomarkers of Graft Dysfunction?

“…At least during the first week, graft dysfunction did not reflect impaired clearance of ADPN, suggesting that factors other than renal function may be involved. A study from Song and coworkers [34] demonstrated a decline in circulating ADPN levels during the initial 72 h after a subtotal nephrectomy in mice with renal failure, associated to down regulation of ADPN. Following this reasoning, we can also speculate that the decrease of circulating ADPN levels observed within the first week after KTx could be due to two different mechanisms according to graft function: enhanced filtration of circulating ADPN and urinary excretion in prompt graft patients; and decline in local expression of ADPN in glomerular endothelium as a result of amplified ischemia-reperfusion injury that usually describes DGF.…”

Role of ASM/Cer/TXNIP Signaling Module in the NLRP3 Inflammasome Activation

“…A plethora of stress stimuli generate excessive ceramide through sphingolipid metabolism. As a secondary signaling molecule, it activates the signal transduction required for the occurrence of biological processes such as in ammation, apoptosis, and cellular differentiation [21,22]. Accumulating evidence has validated that the ceramide accumulation triggers the assembly and activation of NLRP3 in ammasome in various pathological conditions [7,8].…”