Zinc deficiency induces hypertension by paradoxically amplifying salt sensitivity under high salt intake in mice.

BACKGROUND: Hypertension is one of the major etiologies that cause chronic kidney disease (CKD) and can exacerbate kidney dysfunction. Zinc is an essential trace element playing a role in blood pressure regulation, and zinc deficiency, a common comorbidity in patients with CKD, can cause hypertension. However, the precise mechanism underlying zinc deficiency-induced hypertension is unknown. Sodium (Na+) retention due to inappropriate Na+ reabsorption in the renal tubule is the principal pathophysiology of hypertension. Therefore, this study aimed to investigate the association between zinc deficiency and salt sensitivity. METHODS: Adult mice were fed a zinc-adequate (ZnA) or zinc-deficient (ZnD) diet combined with/without high salt in drinking water (HS) for 4 weeks (n = 6 each). Changes in blood pressure, urinary sodium excretion, and the expressions of the proximal tubular Na+ transporter, Na+/H+ exchanger 3 (NHE3), which mostly contributes to filtered Na+ reabsorption and the downstream Na+-Cl- transporter (NCC) were analyzed. RESULTS: Urinary Na+ excretion significantly increased in ZnD mice, indicating that zinc deficiency causes natriuresis. NHE3 expressions were significantly suppressed, whereas NCC was upregulated in ZnD mice. Interestingly, the combination of high salt and ZnD diet (HS-ZnD) reversed the urinary Na+ loss. The NCC remained activated and NHE3 expressions paradoxically increased in HS-ZnD mice compared with those fed the combination of high salt and ZnA diet. In addition, blood pressure significantly increased only in HS-ZnD mice. CONCLUSION: The combination of zinc deficiency and high salt causes hypertension. Zinc is associated with salt-sensitivity, potentially through NHE3 and NCC regulation.

Renal tubular acidosis without interstitial nephritis in Sjögren's syndrome: a case report and review of the literature.

BACKGROUND: Renal tubular acidosis is the principal clinical feature associated with tubulointerstitial nephritis in patients with primary Sjögren's syndrome. Renal tubular dysfunction due to interstitial nephritis has been considered the underlying pathophysiology connecting renal tubular acidosis and primary Sjögren's syndrome. However, the detailed mechanisms underlying the pathophysiology of renal tubular acidosis in primary Sjögren's syndrome is not fully understood. CASE PRESENTATION: A 30-year-old woman was admitted with complaints of weakness in the extremities. The patient was hospitalized thirteen years earlier for similar issues and was diagnosed with hypokalemic paralysis due to distal renal tubular acidosis with primary Sjögren's syndrome. This diagnosis was based on a positive Schirmer's test. Besides, anti-Sjögren's syndrome-related antigen A was also detected. Laboratory tests indicated distal RTA; however, a renal biopsy showed no obvious interstitial nephritis. Laboratory tests conducted during the second admission indicated distal renal tubular acidosis. Therefore, a renal biopsy was performed again, which revealed interstitial nephritis. Histological analysis of acid-base transporters revealed the absence of vacuolar type H+-ATPases in the collecting duct. The vacuolar type H+-ATPase was also absent in the past renal biopsy, suggesting that the alteration in acid-base transporters is independent of interstitial nephritis. CONCLUSIONS: This case study demonstrates that vacuolar-type H+-ATPases are associated with distal renal tubular acidosis, and distal renal tubular acidosis precedes interstitial nephritis in patients with primary Sjögren's syndrome.

Steatosis is involved in the progression of kidney disease in a high-fat-diet-induced non-alcoholic steatohepatitis mouse model.

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.

Creatinine generation rate can detect sarcopenia in patients with hemodialysis.

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.

Skeletal muscle mass is associated with erythropoietin response in hemodialysis patients.

BACKGROUND: Hyporesponsiveness to erythropoietin stimulating agent (ESA) is associated with poor outcomes in patients with chronic kidney disease. Although ESA hyporesponsiveness and sarcopenia have a common pathophysiological background, clinical evidence linking them is scarce. The purpose of the study was to investigate the relationship between ESA responsiveness and skeletal muscle mass in hemodialysis patients. METHODS: This cross-sectional study analyzed 70 patients on maintenance hemodialysis who were treated with ESA. ESA responsiveness was evaluated by erythropoietin resistance index (ERI), calculated as a weekly dose of ESA divided by body weight and hemoglobin (IU/kg/week/dL), and a weekly dose of ESA/hemoglobin (IU/week/dL). A dose of ESA is equivalated to epoetin ß. Correlations between ESA responsiveness and clinical parameters including skeletal muscle mass were analyzed. RESULTS: Among the 70 patients, ERI was positively correlated to age (p < 0.002) and negatively correlated to height (p < 0.001), body weight (p < 0.001), BMI (p < 0.001), skeletal muscle mass (p < 0.001), transferrin saturation (TSAT) (p = 0.049), and zinc (p = 0.006). In the multiple linear regression analysis, TSAT, zinc, and skeletal muscle mass were associated with ERI and weekly ESA dose/hemoglobin. CONCLUSIONS: Skeletal muscle mass was the independent predictor for ESA responsiveness as well as TSAT and zinc. Sarcopenia is another target for the management of anemia in patients with hemodialysis.

Feasibility of computed tomography-based assessment of skeletal muscle mass in hemodialysis patients.

BACKGROUND: Sarcopenia is a major health issue especially in patients on maintenance hemodialysis. Low skeletal muscle mass is included in the diagnostic criteria for sarcopenia. The skeletal muscle mass is usually evaluated by modalities such as bioimpedance analysis (BIA) or dual-energy X-ray absorptiometry, however the assessment of skeletal muscle mass using computed tomography (CT) images has not been established. The purpose of the study was to investigate the feasibility of the assessment of skeletal muscle mass using CT images in hemodialysis patients. METHODS: Skeletal muscle mass index (SMI) was measured by BIA and psoas muscle index (PMI) was measured by cross-sectional CT images in 131 patients. The relationship between SMI and PMI and the diagnostic ability of PMI for low muscle mass were evaluated. Furthermore, the patients were followed up and long-term survival in patients with low and high PMI were compared. RESULTS: PMI measured at the L3 vertebral level was strongly correlated with SMI (r = 0.597, p < 0.001). Age, sex, and SMI were the influencing factors for PMI. Patients with low PMI showed higher incidence rates of mortality during the follow up. CONCLUSIONS: PMI assessed by CT image can be an alternative to BIA in patients on hemodialysis.

A novel method for assessing the renal biopsy specimens using an activatable fluorescent probe.

Gamma-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) is an activatable fluorescent probe that can be activated by γ-glutamyltranspeptidase (GGT). The expression of GGT in the kidney, which is one of the major organs exhibiting enhanced GGT expression, is exclusively localised to the cortex. Here, we aimed to investigate the feasibility of gGlu-HMRG as a probe for the on-site assessment of renal biopsy specimens. gGlu-HMRG fluorescent probe was applied to the renal proximal tubular epithelial cells and cortical collecting duct cells in vitro, mouse kidneys ex vivo, and human biopsy specimens. In addition, the fluorescence intensities in the cortex and the medulla were comparatively evaluated in the biopsy specimens. The fluorescence signal was rapidly detected in the renal proximal tubular epithelial cells, whereas that in the cortical collecting duct cells was not detected. The fluorescence signal was detected in the mouse kidneys ex vivo without markedly affecting the tissue morphology. In the human biopsy specimens, the fluorescence signal in the cortex was significantly distinct from that in the medulla (p < 0.05). Thus, this fluorescent probe can be used to distinctly identify the renal cortex in the biopsy specimens.

Prognostic Value of Neutrophil-To-Lymphocyte Ratio and Platelet-To-Lymphocyte Ratio for Renal Outcomes in Patients with Rapidly Progressive Glomerulonephritis.

BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) is a syndrome characterized by a rapid decline in renal function that often causes end-stage renal disease. Although it is important to predict renal outcome in RPGN before initiating immunosuppressive therapies, no simple prognostic indicator has been reported. The aim of this study was to investigate the associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to renal outcomes in patients with RPGN. METHODS: Forty-four patients with a clinical diagnosis of RPGN who underwent renal biopsy were enrolled. The relationships between NLR and PLR and renal outcome after 1 year were investigated. RESULTS: NLR and PLR were significantly higher in patients with preserved renal function in comparison to patients who required maintenance hemodialysis (p < 0.05 and p < 0.01, respectively). An NLR of 4.0 and a PLR of 137.7 were the cutoff values for renal outcome (area under the curve, 0.782 and 0.819; sensitivity, 78.4% and 89.2%; specificity, 71.4% and 71.4%, respectively). Furthermore, an NLR of 5.0 could predict recovery from renal injury in patients requiring hemodialysis (area under the curve, 0.929; sensitivity, 83.3%; specificity, 85.7%). CONCLUSION: NLR and PLR could be candidates for predicting renal outcomes in patients with RPGN.

Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules.

BACKGROUND: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin. METHODS: Male FLS-ob/ob mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated. RESULTS: The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis. CONCLUSIONS: ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH.

Construction and characterization of a tissue-engineered oral mucosa equivalent based on a chitosan-fish scale collagen composite.

This study was designed to (1) assess the in vitro biocompatibility of a chitosan-collagen composite scaffold (C3) constructed by blending commercial chitosan and tilapia scale collagen with oral mucosa keratinocytes, (2) histologically and immunohistochemically characterize an ex vivo-produced oral mucosa equivalent constructed using the C3 (EVPOME-C), and (3) compare EVPOME-C with oral mucosa constructs utilizing AlloDerm® (EVPOME-A), BioMend® Extend™ (EVPOME-B), and native oral mucosa. C3 scaffold had a well-developed fibril network and a sufficiently small porosity to prevent keratinocytes from growing inside the scaffold after cell-seeding. The EVPOME oral mucosa constructs were fabricated in a chemically defined culture system. After culture at an air-liquid interface, EVPOME-C and EVPOME-B had multilayered epithelium with keratinization, while EVPOME-A had a more organized stratified epithelium. Ki-67 and p63 immunolabeled cells in the basal layer of all EVPOMEs suggested a regenerative ability. Compared with native oral mucosa, the keratin 15 and 10/13 expression patterns in all EVPOMEs showed a less-organized differentiation pattern. In contrast to the ß1-integrin and laminin distribution in EVPOME-A and native oral mucosa, the subcellular deposition in EVPOME-C and EVPOME-B indicated that complete basement membrane formation failed. These findings demonstrated that C3 has a potential application for epithelial tissue engineering and provides a new potential therapeutic device for oral mucosa regenerative medicine.