Zhao Hu

Grape seed proanthocyanidin extract protects from cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis

Cisplatin (CP) is used as an antineoplastic drug in the clinic, but its nephrotoxicity limits its use. Grape seed proanthocyanidin extract (GSPE) is a powerful antioxidant. In this study, we investigated whether GSPE can prevent CP-induced nephrotoxicity and explored the underlying mechanism. Male C57/BL6 mice were randomly divided into four groups: control group (N), CP group (C), receiving an intraperitoneal (ip) injection of 20 mg/kg CP, GSPE group (G), receiving an intragastric (ig) dose of 500 mg/kg GSPE, and CP+GSPE group (C+G), where ig administration of GSPE was performed 30 min prior to ip injection of CP, followed by an additional ig administration of GSPE 72 h later. Blood and kidney samples were collected 120 h after treatment. The pathological changes in the kidney were examined by periodic acid-Schiff (PAS) staining, while the protein levels of glucose-regulated protein 78 (GRP78), phosphorylated-extracellular signal-regulated kinase (p-ERK) and caspase-12 were examined by western blotting and immunohistochemical staining. Apoptosis was examined by a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Compared to the CP group, the CP+GSPE group had a significant decrease in the level of blood urea nitrogen (BUN), serum creatinine (Scr) and reduced renal index (RI) (P<0.05), and showed limited histopathological damage. The number of TUNEL-positive cells was significantly reduced in the CP+GSPE group compared to the CP group (P<0.05), and the protein expression of GRP78, p-ERK and caspase-12 was significantly reduced in the CP+GSPE group (P<0.05). We conclude that GSPE can protect the renal function from CP-induced nephrotoxicity and can attenuate the endoplasmic reticulum (ER) stress-induced apoptosis via regulation of the caspase-12 pathway.

Resveratrol Attenuates Early Diabetic Nephropathy by Down-Regulating Glutathione S-Transferases Mu in Diabetic Rats

Diabetic nephropathy (DN) is the major cause of end-stage renal disease. Resveratrol has been shown to ameliorate hyperglycemia in diabetic rats. However, the effects of resveratrol on DN remain unknown. The aim of the present study is to investigate the effects of resveratrol on early-stage DN. Diabetes was induced by streptozotocin injection in male Wistar rats. The diabetic rats were treated with resveratrol at a dose of 20 mg/kg body weight for 8 weeks. Plasma glucose, creatinine, kidney/body weight ratio, and 24-h urinary protein were determined. The renal pathological changes were examined with periodic acid Schiff staining, and renal mesangial cells were cultured in high glucose concentrations with indicated concentrations of resveratrol (2.5, 5.0, and 10.0 μmol/L). The proliferation of mesangial cells was evaluated by methylthiazoletetrazolium assay. Expressions of glutathione S-transferases Mu (GSTM) and nuclear factor erythroid 2-related factor 2 (Nrf2) were detected by western blot, and apoptosis was analyzed using a flow cytometer. Resveratrol reduced plasma glucose, creatinine, and urinary protein excretion, and attenuated renal hypertrophy. Moreover, resveratrol also reduced the expression of GSTM in diabetic rats. In vitro, resveratrol inhibited the proliferation of mesangial cells caused by high glucose and down-regulated GSTM and Nrf2 expressions in a dose-dependent manner. These findings suggest that resveratrol help prevent the progression of DN. The renoprotection by resveratrol is in part mediated through the inhibition of high glucose-induced rat mesangial cell proliferation and downregulation of GSTM expression.

Relationship Between Psychiatric Disorders and Quality of Life in Nondialysis Patients With Chronic Kidney Disease

Background:The aim of this study was to investigate the relationship between psychiatric disorders (anxiety and depression) and quality of life (QOL) in nondialysis patients with chronic kidney disease (CKD). Methods:QOL was evaluated in a sample of 57 nondialysis patients with CKD using the 36-item Short Form Health Survey questionnaire comprising 8 scales, including the physical component summary and mental component summary measures. Depression and anxiety were estimated using the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale, respectively. Results:Depression and anxiety scores were negatively correlated with 7 of the 8 scales of the Short Form 36 questionnaire, and with the physical component summary and mental component summary scores, despite 38.6% patients with depression and 54.4% with anxiety, whereas QOL in the depression group, the anxiety group, and the anxiety and depression comorbid group was lower than that for those without the corresponding psychiatric disorders (P < 0.05). Conclusions:This study demonstrates that depression and anxiety, commonly encountered in patients with CKD, could be a risk factor for QOL in these patients.

Epigallocatechin-3-gallate protects against cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis.

Cisplatin (CP)-induced nephrotoxicity hampers its application in clinic. Green tea, particularly its predominant polyphenolic constituent epigallocatechin-3-gallate (EGCG), possesses anti-inflammatory, antioxidant, and anti-apoptotic properties. The present study was designed to investigate the protective effects of EGCG against CP-induced nephrotoxicity in mice. Male C57/BL6 mice in different groups received single injection of CP (20 mg/kg) and EGCG (100 mg/kg) in various sets and kidney tissues and blood were collected after killing. Then, samples were used for biochemical and immunohistochemical assay. Our results showed EGCG decreased biochemical factors and immunohistochemical damage induced by CP. Besides, expression of phosphorylated-extracellular signal-regulated kinase (p-ERK), glucose-regulated protein 78 (GRP78), caspase-12, and apoptosis of kidney were decreased by EGCG via inhibition of endoplasmic reticulum (ER) stress-induced apoptosis.

Resveratrol attenuates acute kidney injury by inhibiting death receptor‑mediated apoptotic pathways in a cisplatin‑induced rat model.

Acute kidney injury is a clinical syndrome characterized by a loss of renal function and acute tubular necrosis. Resveratrol exerts a wide range of pharmacological effects based on its anti-inflammatory, antioxidant and cytoprotective properties. The present study aimed to evaluate whether resveratrol attenuates acute kidney injury in a cisplatin-induced rat model and to investigate the potential mechanisms involved. Rats were randomly divided into four treatment groups: Control, cisplatin, resveratrol, and cisplatin plus resveratrol. Rats exposed to cisplatin displayed acute kidney injury, identified by analysis of renal function and histopathological observation. Resveratrol significantly ameliorated the increased serum creatinine, blood urea nitrogen, renal index and histopathological damage induced by cisplatin. Furthermore, compared with untreated control animals, cisplatin lead to significantly increased expression of Fas ligand, tumor necrosis factor-α (TNF-α), caspase-8 and Bcl-2 associated protein X apoptosis regulator (Bax), and decreased expression of anti-apoptosis regulators, BH3 interacting domain death agonist (BID) and B cell lymphoma 2 apoptosis regulator (Bcl-2). Administration of resveratrol significantly reversed the cisplatin-induced alteration in these apoptosis-associated proteins. In conclusion, these findings suggest that resveratrol attenuates cisplatin-induced acute kidney injury through inactivation of the death receptor-mediated apoptotic pathway, and may provide a new therapeutic strategy to ameliorate the process of acute kidney injury.

Mycophenolate mofetil ameliorates diabetic nephropathy through epithelial mesenchymal transition in rats.

Recent studies in animal models have revealed that mycophenolate mofetil (MMF) has certain protective effects against experimental diabetic nephropathy. The present study therefore aimed to investigate the hypothesis that diabetic nephropathy may be ameliorated by mycophenolate mofetil and benazepril treatment alone or in combination, and identify the potential underlying mechanisms in a rat model. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin. Rats were subsequently treated with benazepril, MMF or a combination of the two drugs, and blood glucose, normalized kidney weight, urine protein and serum creatinine were determined. The pathological changes in renal tissue were also observed. In addition, indices of epithelial mesenchymal transition, including α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β1 expression, were examined. Normalized kidney weight, urine protein and serum creatinine levels were significantly improved in the diabetic rats treated with benazepril or mycophenolate mofetil, compared with those of rats in the untreated diabetic group. Pathological changes in the kidney were detected concurrently with increasing kidney weight and urinary albumin excretion, with a similar trend in variation among groups. In addition, the expression of epithelial mesenchymal transition indices, including α-SMA and TGF-β1, in the renal tubule interstitium were significantly decreased in the benazepril- and MMF-treated groups compared with those of the diabetic group. As expected, the aforementioned indices were markedly lower in the benazepril and MMF combined treatment group than those in the single medication groups. These data suggested that MMF may have a protective role in diabetic nephropathy, and that the underlying mechanism may be partially dependent upon the suppression of the epithelial mesenchymal transition. Furthermore, the combination of benazepril and MMF conferred enhanced efficacy over monotherapies in the treatment of diabetic nephropathy.

Correlation Between Endothelial Dysfunction and Left Ventricular Remodeling in Patients with Chronic Kidney Disease

Background/Aims: To investigate the role of endothelial dysfunction on left ventricular remodeling in patients with chronic kidney disease and to evaluate the correlation between endothelial dysfunction and left ventricular remodeling. Methods: Seventy-three patients with chronic kidney disease as study-group and thirty healthy volunteers as control-group were enrolled in the present study. All patients in both groups had echocardiography examination. The concentration of endothelin-1, nitric oxide, and inducible nitric oxide synthase of serum of all patients and healthy volunteers was measured. The incidence of cardiac structural abnormalities in patients with chronic kidney disease, and the relationship between endothelial dysfunction and cardiac structural abnormalities were analyzed. Results: The incidence of left ventricular hypertrophy, left ventricular concentric remodeling, and left ventricular systolic dysfunction was 65%, 8.33%, and 16.67%, respectively. The level of endothelin-1 and nitric oxide increased in study-group, and the concentration of inducible nitric oxide synthase decreased. There was significant positively relationship between plasma endothelin-1 and left ventricular mass index, interventricular septal thickness, left ventricular diastolic diameter. There was negatively relationship between the level of serum nitric oxide and the maximum flow velocity at the mitral in left ventricular diastolic stage. There was not any correlation between inducible nitric oxide synthase with left ventricular remodeling. Conclusions: The results showed that there was a higher incidence of left ventricular hypertrophy in patients with chronic kidney disease. Endothelin-1 and nitric oxide played an important role on the development of left ventricular hypertrophy. i 2014 S. Karger AG, Basel

A comparative study of the renoprotective effects of benidipine and valsartan in primary hypertensive patients with proteinuria.

OBJECTIVE To compare the renoprotective effects of the calcium channel blocker (CCB) benidipine (CAS 105979-17-7) and the angiotensin II receptor blocker (ARB) valsartan (CAS 137862-53-4) in primary hypertensive patients with proteinuria. METHODS 236 patients with primary hypertension were randomly divided into different groups and were administered either benidipine or valsartan. The alterations of the glomerular filtration rate (GFR) and proteinuria were compared between the different groups. RESULTS Valsartan could decrease the level of proteinuria significantly as compared with that in benidipine-treated hypertensive patients with proteinuria at levels <1 g/24 h (P < 0.01). There was no significant difference of the effects of benidipine and valsartan on proteinuria reduction in hypertensive patients with proteinuria at levels 1-3 g/24 h. There was no significant difference of the effects of benidipine and valsartan on GFR in benidipine- and valsartan-treated patients. CONCLUSION The results showed that valsartan was more effective in decreasing the levels of proteinuria in hypertensive patients with proteinuria at an early stage of nephropathy. The renoprotective effects of benidipine and valsartan in primary hypertensive patients with proteinuria were similar.

Clindamycin-induced Kidney Diseases: A Retrospective Analysis of 50 Patients

Objective There are many adverse reactions due to clindamycin, but kidney diseases (acute kidney injury, AKI) are uncommon. However, in recent years, the rate of clindamycin-induced kidney diseases has increased. We analyzed 50 patients with clindamycin-induced kidney diseases retrospectively, and investigated the characteristics of these kidney diseases in order to provide a reference for rational clinical drug use and to reduce drug-induced organ damage. Methods We investigated 50 patients diagnosed with clindamycin-induced kidney diseases retrospectively at the Department of Nephrology, Shandong University Qilu Hospital, from January 2009 to December 2013. The parameters included in our study were age, sex, clinical manifestations, efficacy and prognosis. Results All patients were diagnosed with clindamycin-induced kidney diseases within 48 hours of the application of clindamycin at 1.0-2.0 g/day. The patients included 29 women and 21 men. Most of the enrolled patients were 20-59 years old. Fifty-one patients were diagnosed with AKI stage 3 upon admission. Thirty-three had episodes of gross hematuria, but fever, skin rash and eosinophilia were rare. Urine analysis revealed mild proteinuria and severe tubular dysfunction. In the majority of patients, AKI was severe and required renal replacement therapy, but renal function in all patients had recovered significantly two months after discharge. Conclusion Clindamycin-induced AKI is largely reversible and is associated with episodes of gross hematuria. Clinicians should use clindamycin rationally and reduce the incidence of adverse reactions.

Inhibitory effect of resveratrol on advanced glycation end products-induced mesangial cell proliferation

Diabetic nephropathy (DN) is the major cause of end-stage renal disease. An important histological hallmark of DN is proliferation of mesangial cells, and as a result, the expansion of extracellular matrix in the mesangium. Resveratrol has been shown to ameliorate hyperglycemia in diabetic rats. However, the effects of resveratrol on DN remain unknown. The aim of the present study is to investigate the effects of resveratrol on mesangial cell proliferation induced by advanced glycation end products (AGEs). Cultured rat mesangial cells were exposed to AGEs in the absence and presence of indicated concentrations of resveratrol (2.5, 5.0 and 10.0 μmol/L). The proliferation of mesangial cells was assayed by Methylthiazoletetrazolium (MTT) assay. Cell cycle and apoptosis were analyzed using flow cytometry. Expressions of glutathione S-transferases Mu (GSTM) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were detected by Western blot. Resveratrol inhibited proliferation of mesangial cells caused by AGEs, and down-regulated GSTM and Nrf2 expressions in a dose-dependent manner. S phase cell number significantly increased in the resveratrol treated groups compared with those in the AGEs group. Resveratrol inhibited mesangial cell proliferation induced by AGEs. The inhibitory effects of resveratrol were mediated in part through suppressing cell growth by arresting cells at the S phase of the cell cycle and down-regulating GSTM and Nrf2 expression. These findings suggested that resveratrol had potential preventive effects on the process of DN.