SIRPα Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling. METHODS: SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. RESULTS: We demonstrate that SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. CONCLUSIONS: Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.

Progress in the management of patients with diabetes and chronic kidney disease.

PURPOSE OF REVIEW: Diabetic kidney disease is the most common cause of chronic kidney disease (CKD) and end-stage kidney disease in the world. Risk factor modification, glucose control, and renin-angiotensin-aldosterone system blockade have remained the standard of care for 2 decades. New therapeutic agents have emerged in recent years, demonstrating kidney and cardiovascular benefits, and herein we review recent clinical trials on this topic. RECENT FINDINGS: After the publication of several cardiovascular outcome trials for sodium-glucose cotransporter 2 inhibitors (SGLT-2i), new trials have focused ON primary kidney-specific outcomes demonstrating safety and benefits among patients with proteinuric CKD; patients with or without diabetes, and heart failure with preserved ejection fraction (HFpEF) respectively. Similarly, nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) and glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) have improved cardiovascular and kidney outcomes. Recently, clinical practice guidelines have also been updated to reflect this new evidence. SUMMARY: In summary, SGLT-2i, GLP-1 RAs, and ns-MRAs have demonstrated cardiovascular and kidney benefits, including all-cause and cardiovascular mortality, progression to end-stage kidney disease, and hospitalizations for heart failure exacerbation among diverse patient population.

The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease.

Chronic kidney disease (CKD) and related inflammatory responses stimulate protein-energy wasting, a complication causing loss of muscle mass. Primarily, muscle wasting results from accelerated protein degradation via autophagic/lysosomal and proteasomal pathways, but mechanisms regulating these proteolysis pathways remain unclear. Since dephosphorylation of FoxOs regulates ubiquitin/proteasome protein metabolism, we tested whether a novel nuclear phosphatase, the small C-terminal domain phosphatase (SCP) 4, regulates FoxOs signaling and, in turn, muscle wasting. In cultured mouse myoblast cells, SCP4 overexpression stimulated proteolysis, while knockdown of SCP4 prevented the proteolysis stimulated by inflammatory cytokines. SCP4 overexpression led to nuclear accumulation of FoxO1/3a followed by increased expression of catabolic factors including myostatin, Atrogin-1, and MuRF-1, and induction of lysosomal-mediated proteolysis. Treatment of C2C12 myotubes with proinflammatory cytokines stimulated SCP4 expression in an NF-κB-dependent manner. In skeletal muscle of mice with CKD, SCP4 expression was up-regulated. Similarly, in skeletal muscle of patients with CKD, SCP4 expression was significantly increased. Knockdown of SCP4 significantly suppressed FoxO1/3a-mediated expression of Atrogin-1 and MuRF-1 and prevented muscle wasting in mice with CKD. Thus, SCP4 is a novel regulator of FoxO transcription factors and promotes cellular proteolysis. Hence, targeting SCP4 may prevent muscle wasting in CKD and possibly other catabolic conditions.

Parathyroid hormone stimulates adipose tissue browning: a pathway to muscle wasting.

PURPOSE OF REVIEW: Studying organ-to-organ communications (i.e. crosstalk) uncovers mechanisms regulating metabolism in several tissues. What is missing is identification of mediators of different catabolic conditions contributing to losses of adipose and muscle tissues. Identifying mediators involved in organ-to-organ crosstalk could lead to innovative therapeutic strategies because several disorders such as chronic kidney disease (CKD), cancer cachexia, and other catabolic conditions share signals of worsening metabolism and increased risk of mortality. RECENT FINDINGS: A recent breakthrough published in Cell Metabolism leads to the conclusion that parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) cause 'browning' of white adipose tissue plus energy production via activation of uncoupling protein-1. Browning was associated with muscle wasting in mouse models of cancer and CKD. The pathway to browning includes PTH/PTHrP activation of protein kinase A (PKA) and lost muscle mass via the ubiquitin proteasome proteolytic system (UPS). SUMMARY: The results suggest that crosstalk between muscle and fat contributes in a major way to tissue catabolism. The pathway initiated by PTH or PTHrP is novel and it suggests potential interrelationships that control metabolism in other catabolic conditions. Identifying how the parathyroid hormone-PKA-UPS axis relates to obesity, type 2 diabetes, and other insulin-resistant conditions remains unclear.

Molecular mechanisms of insulin resistance in chronic kidney disease.

Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identify the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids, and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging, and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to the activation of different E3 ubiquitin ligases, which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD.

A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome.

High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and Aim2-/- mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the Aim2-/--HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca2+-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in Aim2-/- mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca2+-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca2+-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.

Interactions between p-Akt and Smad3 in injured muscles initiate myogenesis or fibrogenesis.

In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine whether impaired IGF signaling initiates muscle fibrosis, we generated IGF-IR(+/-) heterozygous mice by crossing loxP-floxed IGF-IR (exon 3) mice with MyoD-cre mice. IGF-IR(+/-) mice were studied because we were unable to obtain homozygous IGF-IR-KO mice. In IGF-IR(+/-) mice, both growth and expression of myogenic genes (MyoD and myogenin; markers of satellite cell proliferation and differentiation, respectively) were depressed. Likewise, in injured muscles of IGF-IR(+/-) mice, there was impaired regeneration, depressed expression of MyoD and myogenin, and increased expression of TGF-ß1, α-SMA, collagen I, and fibrosis. To uncover mechanisms stimulating fibrosis, we isolated satellite cells from muscles of IGF-IR(+/-) mice and found reduced proliferation and differentiation plus increased TGF-ß1 production. In C2C12 myoblasts (a model of satellite cells), IGF-I treatment inhibited TGF-ß1-stimulated Smad3 phosphorylation, its nuclear translocation, and expression of fibronectin. Using immunoprecipitation assay, we found an interaction between p-Akt or Akt with Smad3 in wild-type mouse muscles and in C2C12 myoblasts; importantly, IGF-I increased p-Akt and Smad3 interaction, whereas TGF-ß1 decreased it. Therefore, in muscles of IGF-IR(+/-) mice, the reduction in IGF-IR reduces p-Akt, allowing for dissociation and nuclear translocation of Smad3 to enhance the TGF-ß1 signaling pathway, leading to fibrosis. Thus, strategies to improve IGF signaling could prevent fibrosis in catabolic conditions with impaired IGF signaling.

Signal regulatory protein-α interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease.

Insulin resistance from chronic kidney disease (CKD) stimulates muscle protein wasting but mechanisms causing this resistance are controversial. To help resolve this, we used microarray analyses to identify initiators of insulin resistance in the muscles of mice with CKD, glucose intolerance, and insulin resistance. CKD raised mRNAs of inflammatory cytokines in muscles and there was a 5.2-fold increase in signal regulatory protein-α (SIRP-α), a transmembrane glycoprotein principally present in muscle membranes. By immunoprecipitation we found it interacts with the insulin receptor and insulin receptor substrate-1 (IRS-1). Treatment of myotubes with a mixture of inflammatory cytokines showed that SIRP-α expression was increased by a NF-κB-dependent pathway. Blockade of NF-κB using a small-molecule chemical inhibitor or a dominant-negative IKKß reduced cytokine-induced SIRP-α expression. The overexpression of SIRP-α in myotubes impaired insulin signaling and raised proteolysis while SIRP-α knockdown with siRNAs in skeletal muscle cells increased tyrosine phosphorylation of the insulin receptor and IRS-1 despite inclusion of cytokines. This led to increased p-Akt and suppression of protein degradation. Thus, SIRP-α is part of a novel mechanism for inflammation-mediated insulin resistance in muscle. In catabolic conditions with impaired insulin signaling, targeting SIRP-α may improve insulin sensitivity and prevent muscle atrophy.

Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin.

Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.