Kensei Taguchi

Receptor for advanced glycation endproducts and progressive kidney disease.

Purpose of reviewReceptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily, which binds not only to advanced glycation endproducts, but also to high-mobility group box-1, S100/calgranulins, amyloid fibrils, and lipopolysaccharide. We discuss the pathophysiological role of RAGE in both diabetic and nondiabetic progressive renal diseases, and its potential use for therapeutic interventions in these devastating disorders. Recent findingsAlthough initial studies about RAGE focused on diabetic nephropathy, a number of recent findings have revealed that RAGE also actively participates in the pathogenesis of nondiabetic progressive renal diseases, including hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, autosomal dominant polycystic kidney disease, renal amyloidosis, and septic acute kidney injury. Furthermore, blocking the RAGE by a neutralizing antibody or genetic deletion of RAGE was found to prevent the development and progression of various renal disorders. SummaryThe interaction of several RAGE ligands with RAGE plays a role in a broad range of progressive kidney diseases. The blockade of the various RAGE ligands–RAGE interactions might be a novel therapeutic strategy for preventing the development and progression of numerous progressive kidney diseases.

Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury

Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2′-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury–induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.

DNA-aptamers raised against AGEs as a blocker of various aging-related disorders

A non-enzymatic reaction between sugars or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules, which could impair their structural integrity and function. This process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions, such as rearrangements and dehydration to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress in a physiological aging process and at an accelerated rate under hyperglycemic, inflammatory and oxidative stress conditions. There is a growing body of evidence that AGEs and their receptor RAGE interaction play a role in the pathogenesis of various devastating disorders, including cardiovascular disease, Alzheimer’s disease, insulin resistance, osteoporosis and cancer growth and metastasis. Furthermore, diet has been recently recognized as a major environmental source of AGEs that could also elicit pro-inflammatory reactions, thereby being involved in organ damage in vivo. Therefore, inhibition of AGE formation and/or blockade of the interaction of AGEs with RAGE may be a novel therapeutic target for aging-related disorders. This article discusses a potential utility of DNA-aptamers raised against AGEs for preventing aging and/or diabetes-associated organ damage, especially focusing on diabetic microvascular complications, vascular remodeling, metabolic derangements, and melanoma growth and expansion in animal models.

Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.

RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice

The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE–RAGE axis and MR system in kidney derangement remains unclear. We screened DNA-aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE–RAGE axis and Aldo–MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases.

AGEs–RAGE overexpression in a patient with smoking-related idiopathic nodular glomerulosclerosis

We report a case of smoking-related idiopathic nodular glomerulosclerosis (ING) with overexpression of glomerular advanced glycation end products (AGEs) and their receptor (RAGE). A 59-year-old Japanese man with nephrotic syndrome, who had a smoking history of one pack of cigarettes per day for approximately 40 years, presented with a 3-year history of urinalysis abnormalities without clinical evidence of diabetic mellitus. The patient’s leg edema progressively worsened over the previous 2 years, and he was admitted to our hospital. Renal biopsy showed mesangial expansion with diabetic Kimmelstiel–Wilson-like nodular lesions, glomerular basement thickening, and arteriosclerosis. No electron-dense deposits, fibrils, or microtubule deposits were seen in the glomeruli on electron microscopy. Skin AGE level measured using AGE reader was higher in this case than the average level in age-matched Caucasians. In addition, immunohistochemical analysis revealed that N-carboxymethyl lysine, one of the major AGEs, and RAGE were overexpressed and podocin expression was decreased in the peripheral area of the glomerular nodular lesions. These observations suggest that AGEs–RAGE system may be activated in smoking-related ING, possibly leading to the progression of renal dysfunction.

L-carnitine Supplementation Improves Self-rating Depression Scale Scores in Uremic Male Patients Undergoing Hemodialysis

Background: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. Methods: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. Results: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyryl-carnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). Conclusion: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl-carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression.

The Coexistence of Multiple Myeloma-associated Amyloid Light-chain Amyloidosis and Fabry Disease in a Hemodialysis Patient

Fabry disease (FD) is an inherited lysosomal disorder caused by an X-linked α-galactosidase A deficiency. We report the case of a 50-year-old male FD patient on hemodialysis who presented with macroglossia-related speaking difficulty and gastrointestinal symptoms. An endoscopic analysis revealed multiple gastric ulcers, and a histological examination led to a diagnosis of amyloid light-chain amyloidosis. Serum free light-chain and bone marrow analyses detected multiple myeloma (MM). Treatment with bortezomib and dexamethasone significantly improved the patients symptoms. This is the first case to demonstrate a potential pathogenic relationship between FD and MM. The similar gastrointestinal manifestations might have contributed to the diagnostic difficulty.

Accurate estimation of protein/creatinine ratio on urine sample in CKD patients

Chronic kidney diseases (CKD) is common in general population and is associated with increased risk for end stage renal disease (ESRD), its complications and mortality. The number of patients with ESRD requiring maintenance dialysis or transplantation is increasing worldwide and the costs associated with the care of those are estimated to exceed US

Maternal exposure to high-fat and high-fructose diet evokes hypoadiponectinemia and kidney injury in rat offspring.

1 trillion. Therefore, the discovery of novel and accurate biomarker for evaluating the risk of CKD patients is needed. So far, proteinuria and/or albuminuria are widely recognized as a pivotal predictor of risk for the development and progression of CKD and cardiovascular disease (CVD) [1]. Regarding CKD progression, it is well established that reabsorption of urinary protein or albumin after glomerular filtration induces renal tubular damage through the upregulation of proimflammatory and profibrotic cytokines such as regulated upon activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 and tissue growth factor-b, respectively [2]. Indeed, numerous epidemiological studies have demonstrated that proteinuria is a strong and independent predictor of ESRD [3]. Even a slight increase in proteinuria measured by dipstick urinalysis, such as proteinuria (±) for men or proteinuria (?) for women, is also known to be an independent determinant for ESRD [4]. In addition, microalbuminuria closely correlates to the incidence of CVD among patients with diabetes, hypertension or both [5]. Other cohort studies revealed that even a normal range albuminuria could be a strong predictor of CVD among patients with diabetes as well [6]. Interestingly, sustained reduction in microalbuminuria by the treatment with angiotensin converting enzyme inhibitor, with no changes or even rises in blood pressure, reflected reductions in the risk for CVD in patients with diabetes and microalbuminuria [7], suggesting that urinary protein or albumin should be regarded not only as a contributor to accelerate the progression of CKD, but also as an important therapeutic target for renal and cardiovascular protection. Therefore, accurate measurement of urinary protein or albumin excretion, even within a normal range, is required for initial evaluation and follow-up of patients with CKD. As the dipstick urinalysis shows a low specificity and sensitivity for quantification of proteinuria, the direct measurement of protein in 24 h urine (24 hUp) is still now recognized as a standard method for assessing proteinuria and is also considered to be the most reliable. However, the 24-h urine collection is not convenient for outpatients and is subject to collection errors, which might range from 12 to 35 % as reported in previous studies [8]. Since urinary protein/creatinine ratio [UP/Ucr ratio (g/gCr)] has shown to be correlated with 24hUp [9], UP/Ucr is commonly used in clinical situation instead of 24hUp. UP/Ucr ratio is recognized as a 1-day urinary protein excretion based on the assumption that daily creatinine excretion levels remain constant at approximately 1000 mg. Creatine in skeletal muscle is constantly converted to creatinine in non-enzymatic reaction. Most serum creatinine is eliminated from the kidney in individuals with normal kidney function, which is expected to be constant This comment refers to the article available at doi:10.1007/s10157015-1178-z.