Current Protein and Peptide Science - Volume 18, Issue 12, 2017

The renoprotection of erythropoietin (EPO) and its derivatives such as helix B surface peptide (HBSP) have attracted a great deal of attention from scientists and clinicians alike. The evolutional achievement in the dissociation of tissue protection and erythropoiesis is obtained through HBSP characterisation and synthesis. We performed a series of studies using EPO, as well as HBSP, in a variety of biological models subjected to transplant-related renal injuries such as ischemia reperfusion injury (IRI) and/or immunosuppressant nephrotoxicity. In this short review, we would like to address the effects of EPO in different formats, and its underlying mechanisms with focuses on apoptosis and inflammation in in vitro, ex vivo and in vivo renal injury models, and to further explore potential applications and challenges in humans.

Erythropoietin (EPO), recognized early as a tissue protective agent, can trigger antiinflammatory and anti-apoptotic processes to delimit injury and promote repair by binding tissueprotective receptor (TPR). However, only at a high dosage can EPO exert tissue protective effect, which may elicit severe side-effects at the meantime. Helix B surface peptide (HBSP), a 11-amnio acid sequence derived from the non-erythropoietic helix B of EPO, not only shows higher affinity to TPR but also plays a more specific and powerful role in tissue protection without erythropoietic side-effects. While it has obvious merits, the 2-min plasma half-life of HBSP restricts its application in vivo. Therefore, based on the amino acid sequence of HBSP, we originally designed and synthesized thioethercyclized helix B peptide (CHBP) for an increased resistance to proteolytic degradation as well as an improved tissue protective potency, implying a brighter prospective for translational application. In this review, we will mainly discuss the development from EPO to CHBP, the merits and limitation of CHBP and the probable mechanism mediating tissue protection.

In the past decade, rapid developments in stem cell studies have occurred. Researchers have confirmed the plasticity of bone marrow stem cells and the repair and regeneration effects of bone marrow hematopoietic stem cells on solid organs. These findings have suggested the possibility of using bone marrow stem cell mobilizers to repair and regenerate injured organs. Recent studies on the effects of granulocyte colony-stimulating factor (G-CSF) and Plerixafor (AMD3100) on mouse acute kidney injury models have confirmed that the use of bone marrow stem cell mobilizers may be an effective therapeutic measure. This paper summarizes studies describing the effects of G-CSF and AMD3100 on various acute kidney injury models over the past 10 years.

Acute kidney injury (AKI) is manifested by inflammation, and an early feature in the pathogenesis is the accumulation of immune cells in the kidney. Natural killer T (NKT) cells, a peculiar T cells subtype, serve as a bridge between innate and adaptive immunity. Due to the difference between type I and type II subsets, NKT cells were supposed to play a dual role in IR-related tissue injury. Furthermore, membrane receptors and clinical immunosuppressive agents remain involved in the modulation of NKT cell function. Therefore, regulation of the amount and viability of NKT cells becomes a potential strategy in amelioration of AKI. This review will highlight the recent insights gained into the role and mechanisms of NKT cells in AKI.

Acute kidney injury (AKI) is one of the most common complications in critically ill patients, resulting in high morbidity and mortality. AKI usually occurs after major surgery, severe infection or drug-induced nephrotoxicity and is associated with prolonged hospital stays, increased costs and adverse clinical outcomes. The diagnosis of AKI is currently based on decreased glomerular filtration rate (GFR) and urine output, and increased serum creatinine. Novel biomarkers are required for early identification of patients with AKI to allow timely therapy and improve patient outcomes. With the advent of proteomics and genomics techniques, a vast array of biomarkers are now available in clinical practice.

Acute kidney injury (AKI) is one of the most common complications of various serious conditions, and early diagnosis is therefore critical for the treatment of AKI. Increase of the classic AKI biochemical markers such as serum creatinine is not evident until renal function is irreversibly damaged, which adds to the difficulties of early identification of AKI and results in an increase of the mortality rate. In order to improve the prevention, diagnosis, treatment, and prognosis prediction of AKI, novel early markers of AKI are required. Recent evidence demonstrates that neutrophil gelatinase- associated lipocalin (NGAL) is closely associated with AKI. Several experimental and clinical studies have shown that the expression of urine and serum NGAL increases significantly in AKI. In particular, the urine NGAL level is closely associated with the severity of kidney injury, and could be detected earlier than other AKI markers. Therefore, NGAL shows potential to be a new effective early biochemical marker of AKI. Further studies are needed to confirm the significant advantages of NGAL in the diagnosis of early AKI and its value in clinical applications.

Transcatheter arterial chemoembolization (TACE) is an effective therapy for hepatocellular carcinoma (HCC). However, acute kidney injury (AKI) may occur after TACE due to the contrast agent and cytotoxic anticancer drugs used in this procedure. Post-TACE AKI is not an unusual event, and may adversely affect patient outcome. Coexisting situations including cirrhosis, renal insufficiency, diabetes and hypertension play a role in the development of HCC, and may predispose patients to AKI after TACE. Most post-TACE are transient and reversible, while prolonged AKI may predict a decreased survival. The best strategy to manage post-TACE AKI is prevention. Patients, before undergoing TACE, should be carefully assessed. In this study, we reviewed the current literature published in English about the incidence rate, risk factors, management and prognosis of AKI in patients with HCC undergoing TACE for a better understanding of this complication.

The current lack of complete understanding of the pathogenesis of acute kidney injury (AKI) is a significant barrier to its early diagnosis and treatment. Cell cycle arrest plays an important role in the protection of renal tubular epithelial cells and maladaptive repair following AKI. G1 phase cell arrest serves as a protective mechanism following AKI, avoiding replication of damaged DNA. Insulinlike growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) are closely associated with G1 cell cycle arrest during the very early phase of cellular damage and can serve as an ideal biomarker to predict AKI. However, sustained cell cycle arrest after severe AKI may result in cell senescence and maladaptive repair, with typical characteristics of the development of cell cycle arrest in the gap 2 (G2) or mitotic (M) phase. Markers of cell cycle arrest signal and spread the “alarm” from the site of injury to adjacent cells in an autocrine or paracrine manner, giving rise to abnormal amplification and release of profibrogenic factors, activation of pericytes/perivascular fibroblasts, and eventually fibrosis. Therefore, cell cycle regulation has become a potentially new target for the prevention and treatment of AKI. In this review, we summarize the characteristics of the cell cycle following AKI and the markers of cell cycle arrest that enable the early detection of AKI. We also discuss how to prevent the progression of chronic kidney disease (CKD) by regulating cell cycle arrest.

Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is released in response to osmotic and non-osmotic stimuli and plays a key role in many physiologic and pathologic processes. The main function of AVP is the control of fluid homeostasis by inducing water conservation by the kidney, but it also stimulates arteriolar vasoconstriction and the release of adrenocorticotropic hormone (ACTH). These actions are mediated by different AVP receptors located on various target cells. Produced in hypothalamus from a larger precursor, pre-proAVP, AVP is produced in equimolar amounts to copeptin, a glycopeptide with yet unknown biologic function. Copeptin remains stable in plasma and its circulating concentrations correlate directly with those of AVP. Because AVP is unstable in isolated plasma or serum and its half-life is short, copeptin has become an easily measured surrogate marker reflecting vasopressin concentration. Recently, associations between high circulating copeptin and decline in glomerular filtration rate as well as greater risk of new-onset chronic kidney disease (CKD) have been reported. In addition, copeptin has been shown to be associated with increased risk of complications such as myocardial infarction, heart failure, diabetes mellitus and metabolic syndrome. In this brief review, studies on the prognostic value of copeptin measurement in the general population and in CKD are presented and discussed.

The aggregation of proteins or their digested fragments through β-sheet structures has a great significance because it leads to neurodegenerative diseases, which are a problem of the aging societies of the developed countries. Short peptides are typically used as models to study the formation of specific structures. However, while the formation of α-helical structure was investigated thoroughly, until recently, there have been much fewer studies on the formation of β-structure. In this review, recent experimental and theoretical studies of β-hairpin-forming peptides, both model alaninebased systems, and those based on the fragments of real proteins, are summarized with regard to the role of hydrophobic, local, and Coulombic interactions. It is demonstrated that the presence of charged residues can induce a bent structure not only owing to the formation of salt bridges if oppositely- charged residues present at the ends of a sequence but also through shielding the hydrophobic interior by like-charged residues at the end of the sequence.

The peptide hormone relaxin (RLX), in addition to its effects on reproduction, has been reported to influence gastrointestinal motility. Interestingly, the digestive tract has been shown to express RLX receptors and the hormone appears to exert site-specific effects acting at the neural or at the smooth muscle level, mainly by a nitric oxide (NO)-mediated mechanism. NO, released by the enteric nerves and/or smooth muscle cells, is one of the main mediators of gastrointestinal relaxation. In fact, in murine in vitro preparations, RLX depresses organ motility acting at the neural level in the stomach and at the muscular level in the small intestine; conversely, in the colon, this hormone paradoxically increases contractility operating at both neural and muscle levels. These effects are ascribable to the ability of RLX to selectively regulate the expression of the different nitric oxide synthase (NOS) isoforms in the different gastrointestinal tracts. Furthermore, recent electrophysiological experiments have shown that RLX can directly affect the biophysical properties of ileal and colonic smooth muscle cells. This mini-review is intended to offer an update on the site-related actions of RLX on gastrointestinal tract motility in relation with its site-specific effects on NOS isoforms expression. Based on these properties, RLX might be considered a potential therapeutic approach to gastrointestinal motor dysfunctions related to an altered NO production.

Research interests on amphibian antimicrobial peptides (AMPs) are currently increasing because of their capability to combat microorganisms from both terrestrial and aquatic environments, which are the warehouses of human pathogens. The most remarkable feature of AMPs are their mechanism of action, primarily targeted to anionic membranes. Researchers have postulated many models to describe peptide- membrane interaction, which leads to membrane permeation/intracellular targeting. Despite these models information regarding the relationship between membrane curvature and peptidemembrane interaction is scarce. This relationship could be clearly depicted using the two-state model and interfacial activity model. In the review, we discuss in detail the two state and interfacial activity models and explain the influence of membrane curvature on peptide binding and the membrane interaction of curvature-sensitive peptides. In addition, the models proposed to explain the mechanism of action of membrane lytic and non-lytic AMPs are also reviewed.

Creatine, a very popular supplement among athletic populations, is of growing interest for clinical applications. Since over 90% of creatine is stored in skeletal muscle, the effect of creatine supplementation on muscle metabolism is a widely studied area. While numerous studies over the past few decades have shown that creatine supplementation has many favorable effects on skeletal muscle physiology and metabolism, including enhancing muscle mass (growth/hypertrophy); the underlying mechanisms are poorly understood. This report reviews studies addressing the mechanisms of action of creatine supplementation on skeletal muscle growth/hypertrophy. Early research proposed that the osmotic effect of creatine supplementation serves as a cellular stressor (osmosensing) that acts as an anabolic stimulus for protein synthesis signal pathways. Other reports indicated that creatine directly affects muscle protein synthesis via modulations of components in the mammalian target of rapamycin (mTOR) pathway. Creatine may also directly affect the myogenic process (formation of muscle tissue), by altering secretions of myokines, such as myostatin and insulin-like growth factor-1, and expressions of myogenic regulatory factors, resulting in enhanced satellite cells mitotic activities and differentiation into myofiber. Overall, there is still no clear understanding of the mechanisms of action regarding how creatine affects muscle mass/growth, but current evidence suggests it may exert its effects through multiple approaches, with converging impacts on protein synthesis and myogenesis.