Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. ...Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.
Uromodulin, also known as the Tamm-Horsfall protein, is predominantly expressed in epithelial cells of the kidney. It is secreted mainly in the urine, although small amounts are also found in serum. ...Uromodulin plays an important role in maintaining renal homeostasis, particularly in salt/water transport mechanisms and is associated with salt-sensitive hypertension. It also regulates urinary tract infections, kidney stones, and the immune response in the kidneys or extrarenal organs. Uromodulin has been shown to be associated with the renal function, age, nephron volume, and metabolic abnormalities and has been proposed as a novel biomarker for the tubular function or injury. These findings suggest that uromodulin is a key molecule underlying the mechanisms or therapeutic approaches of chronic kidney disease, particularly nephrosclerosis and diabetic nephropathy, which are causes of end-stage renal disease. This review focuses on the current understanding of the role of uromodulin from a biological, physiological, and pathological standpoint.
Background
Sarcopenia is strongly associated with long-term mortality in patients undergoing hemodialysis. The diagnostic modalities used to assess muscle mass, such as bioimpedance analysis and ...dual-energy X-ray absorption measurement, have limitations for application in patients on hemodialysis. Therefore, there is a need to establish a simple index for assessing muscle mass that can be universally performed in patients on hemodialysis.
Methods
Patients on maintenance hemodialysis were included in this study. Laboratory tests, skeletal muscle mass measured by bioimpedance analysis, and clinical records were obtained retrospectively. The creatinine generation rate (CGR) was calculated from the pre- and postdialysis blood tests using a kinetic model as the index for whole-body muscle mass. Correlations between the CGR and skeletal muscle mass were investigated, and the cut-off value for muscle wasting was determined. Kaplan–Meier survival analysis was performed to investigate the feasibility of the CGR for predicting long-term survival.
Results
Among the 130 patients included, eight were diagnosed with sarcopenia by bioimpedance analysis. The CGR was positively correlated with skeletal muscle mass (
r
= 0.454,
p
< 0.001). Multiple linear regression analysis revealed that age and sex independently influenced the CGR. The patients were classified into two groups according to age- and sex-adjusted CGRs. During a median follow-up period of 32 months, the Kaplan–Meier survival analysis showed that patients with low CGR showed significantly poor long-term prognosis (
p
= 0.002).
Conclusion
The CGR is a simple index for muscle mass and can predict long-term mortality in patients on hemodialysis.
A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it ...has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes.
Endoplasmic reticulum (ER) stress plays a pivotal role in the progression of steatohepatitis. 5-aminolevulinic acid (5-ALA), a precursor in the heme biosynthetic pathway, has recently been reported ...to induce heme oxygenase (HO)-1. HO-1 exerts important cytoprotective actions. In this study, we aimed to explore the therapeutic potential of 5-ALA on palmitate-induced ER stress and lipoapoptosis. Huh-7 cells were treated with palmitic acid (PA) (800 μM) to induce steatosis for eight hours. Steatosis was evaluated by Lipi-green staining. 5-ALA (200 μM) was added with PA. The gene expression levels of the nuclear factor erythroid 2-related factor 2 (
),
, Glucose-regulated protein 78 (
), activating transcription factor 6 (
), PKR-like endoplasmic reticulum kinase (
), inositol-requiring enzyme 1 (
), C/EBP homologous protein (
), and B-cell lymphoma 2 (
) were evaluated by RT-PCR. Caspase-3/7 activity was evaluated by fluorescein active Caspase-3/7 staining. Cell death was evaluated by Annexin V/SYTOX green staining. PA significantly induced steatosis and increased
expression in Huh-7 cells. 5-ALA significantly induced
and decreased
expression.
was subsequently decreased. However,
and
expression were not altered. Anti-apoptotic
expression significantly increased, and Caspase 3/7 activity and cell death also decreased. 5-ALA has a therapeutic potential on hepatic steatosis by suppressing ER stress and lipoapoptosis by attenuating
via
induction.
Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health issues associated with the metabolic syndrome. Although NASH is a known risk factor of CKD, the mechanisms ...linking these two diseases remain poorly understood. We aimed to investigate alterations in the kidney complicated with dyslipidemia in an established NASH mouse model. Male C57BL6/J mice were fed with control diet or high-fat diet (HFD), containing 40% fat, 22% fructose, and 2% cholesterol for 16 weeks. Metabolic characteristics, histological changes in the kidney, endoplasmic reticulum (ER) stress, apoptosis, and fibrosis were evaluated by histological analysis, immunoblotting, and quantitative reverse transcription-polymerase chain reaction. Levels of serum aspartate aminotransferase, alanine aminotransferase, alkali-phosphatase, total cholesterol, and urinary albumin were significantly higher in mice fed with HFD. Remarkable steatosis, glomerular hypertrophy, and interstitial fibrosis were also shown in in the kidney by leveraging HFD. Furthermore, HFD increased the mRNA expression levels of Casp3, Tgfb1, and Nfe2l2 and the protein level of BiP. We observed the early changes of CKD and speculate that the underlying mechanisms that link CKD and NASH are the induction of ER stress and apoptosis. Further, we observed the activation of Nfe2l2 in the steatosis-induced CKD mouse model. This NASH model holds implications in investigating the mechanisms linking dyslipidemia and CKD.
Abstract
The tumour microenvironment (TME) plays an important role in cancer development, progression, and metastasis. Various cytokines are present in the TME in oesophageal cancer. Oesophageal ...stricture is a major complication of endoscopic submucosal dissection (ESD) for oesophageal cancer, and inflammatory cytokines are closely related to its pathogenesis. However, the cytokine crosstalk involved in the oesophageal cancer TME and post-ESD stricture has not been fully elucidated. This study investigated the comprehensive cytokine dynamics following ESD in patients with oesophageal cancer. In addition, the effect of a novel preventive technique for post-ESD stricture, autologous cell sheet engraftment, on cytokine levels was evaluated. Various pro-inflammatory and anti-tumorigenic cytokines were elevated in patients with oesophageal cancer, and ESD transiently influenced cytokine concentrations. IL-1β and TNF-α, two major pro-inflammatory cytokines that induce oesophageal stricture, were significantly suppressed by cell sheet engraftment. In conclusion, this study revealed the distinct cytokine dynamics after ESD in patients with oesophageal cancer, together with the effect of autologous cell sheet engraftment on cytokine fluctuation. These results can accelerate research on the TME and therapeutic strategies for oesophageal cancer.
Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the ...TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin−2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross−talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.
ABSTRACT A significant proportion of patients with infective endocarditis presents with acute renal failure related to infective endocarditis-associated glomerulonephritis (IEAGN). However, the ...clinical presentation of IEAGN differs from that of other infection-related glomerulonephritis (IRGN) with anti-neutrophil cytoplasmic antibody (ANCA) positivity occurring in almost one-third of cases ; therefore, it may be difficult to establish a definitive diagnosis and provide appropriate treatment. This review article provides a comprehensive understanding of the clinical presentation, investigations, histopathology, and treatment/management of IEAGN so that clinicians can keep this differential in mind for patients with fever of unknown origin accompanied by signs and symptoms of acute renal failure.
The Gram-negative diplococcus Neisseria macacae is a commensal bacterium of the mucosal surfaces in humans. A 52-year-old woman receiving continuous ambulatory peritoneal dialysis was admitted ...because of abdominal pain and turbid peritoneal fluid. N. macacae was isolated from peritoneal fluid culture and showed susceptibility to ceftriaxone. Despite appropriate antibiotics, the peritonitis was refractory, leading to the removal of the peritoneal dialysis catheter. We herein report the first case of peritoneal dialysis peritonitis caused by Neisseria macacae and review previous case reports of N. macacae infection in humans.
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