Ameliorative effect of a nano chromium metal-organic framework on experimental diabetic chronic kidney disease.

Metal-Organic Frameworks (MOFs) are a new class of crystalline porous structures which can be used as a novel structure in diverse fields of medical science. Several studies have shown that chromium supplementation can be effective in amelioration of biochemical parameters of diabetes and its renal complications. Therefore, a chromium-containing MOF (DIFc) was synthetized by nanochelating technology in the present study and then its effect on biochemical indices in diabetic rats was evaluated. Diabetes was induced by high-fat diet consumption and streptozotocin (35 mg/kg) injection and then the treatment started 8 weeks after disease induction and continued for 8 weeks. The results showed that DIFc treatment decreased HOMA-IR index, blood urea nitrogen, uric acid and malondialdehyde in plasma samples. This nano MOF also reduced albumin, malondialdehyde and 8-isoprostane in urine specimen, while it increased creatinine clearance. In conclusion, DIFc MOF demonstrated promising results in the present study, indicating that it can be developed and evaluated in future investigations with the aim of designing a novel agent for management of diabetes and its renal complications.

Sodium-glucose co-transporters and diabetic nephropathy: Is there a link with toll-like receptors?

The incidence of diabetes mellitus (DM) has increased alarmingly over the last decades. Despite taking measures aimed at controlling hyperglycaemia and blood pressure, the rate of end-stage renal disease (ESRD) is continually growing. Upon increased amounts of advanced glycation end products (AGEs) and their correspondent receptors (RAGEs), AGE-RAGE axis is over-activated in DM, being the first step in the initiation and propagation of inflammatory cascades. Meanwhile, HMGB1, released from damaged cells in the diabetic kidneys, is the most notable ligand for the highly expressed toll-like receptors (TLRs) and RAGEs. TLRs play an indispensable role in the pathogenesis of diabetic nephropathy. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are hypoglycaemic agents acting on the renal proximal tubules to prevent glucose reabsorption and therefore increase urinary glucose excretion. Besides improving glycaemic control, these hypoglycaemic agents possess direct renoprotective properties. Here, therefore, we review the most recent findings regarding interrelationship between SGLT2 inhibitors and HMGB1-TLR4 axis.

Empagliflozin Attenuates Renal and Urinary Markers of Tubular Epithelial Cell Injury in Streptozotocin-induced Diabetic Rats.

Empagliflozin, a SGLT-2 inhibitor, improves diabetic nephropathy through its pleiotropic anti-inflammatory effects. The present study aims to evaluate empagliflozin effects on renal and urinary levels of tubular epithelial cell injury markers in streptozotocin-induced diabetic rats. Empagliflozin at 10 mg/kg (p.o.) was administered for 4 weeks, beginning 8 weeks after induction of diabetes. Renal function as well as markers of renal tubular epithelial cell injury were assessed in kidney tissue homogenates and urine. Empagliflozin was able to ameliorate diabetes induced elevations in serum cystatin C levels. It also alleviated renal KIM-1/NGAL levels and urinary albumin, α-GST, and RBP excretions. In addition to decreasing urinary levels of cell cycle arrest indices i.e. TIMP-2 and IGFBP7, empagliflozin mitigated acetylated NF-κB levels in renal tissues of diabetic rats. As a whole, these findings reveal empagliflozin capability in improving diabetic nephropathy via ameliorating indices of renal inflammation, injury, and cell cycle arrest on streptozotocin-induced diabetic rats.

Oxidative stress-induced renal telomere shortening as a mechanism of cyclosporine-induced nephrotoxicity.

Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine-A exerts its nephrotoxic side effects via induction of oxidative stress-induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8-hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine-A treatment significantly (P < 0.05) enhanced renal malondialdehyde, 8-hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine-A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine-induced oxidative stress, indicating the potential mechanism of cyclosporine-induced nephrotoxicity.

Soluble Tumor Necrosis Factor Like Weak Inducer of Apoptosis and Vitamin D in Hemodialysis Patients: Relation to Carotid Intima-Media Thickness.

Cardiovascular disease, as the leading cause of patient death with chronic kidney disease, could be predicted by carotid atherosclerosis. The aim of the present study was to evaluate a possible relationship between serum soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and Vitamin D levels with mean right/left carotid intima-media thickness (cIMT), in the hemodialysis (HD) patients. In this cross-sectional study, serums were obtained from 50 stable chronic HD patients and 39 healthy controls. The serum levels of sTWEAK, Vitamin D, intact parathyroid hormone (iPTH) in both groups, and cIMT were determined in HD patients by standard methods. Serum levels of sTWEAK were higher [808.8 (521.6-5032.4) pg/ml vs. 664.4 (487.4-2955.8) pg/ml (p = 0.006)] and Vitamin D levels were lower [13.4 (2.5-153) ng/ml vs. 27.8 (18.4-59.0) ng/ml (p = 0.001)] in the hemodialysis patients than in the healthy control. No important correlation was found between sTWEAK Vitamin D levels (r = 0.010/p = 0.946), and mean right(r = -0.194/p = 0.178) and left (r = 0.061/p = 0.673) cIMT in the HD patients. Our study shows that sTWEAK levels are elevated in HD patients. This elevation has no association with the cIMT.

Autologous transplantation of mesenchymal stromal cells tends to prevent progress of interstitial fibrosis in a rhesus Macaca mulatta monkey model of chronic kidney disease.

BACKGROUND AIMS: Chronic kidney disease (CKD) attributed to cisplatin is well documented. Mesenchymal stromal cells (MSCs) are proven to be renotropic. Although they have been shown to improve function in CKD and reduce fibrosis in different experimental rodent models, their efficiency in primates is unknown. The present study aimed to evaluate the prevention of CKD and reduction of fibrosis in monkeys treated with MSCs after cisplatin nephrotoxicity. METHODS: We induced CKD in adult rhesus Macaca mulatta monkeys by means of intravenous administration of cisplatin. Autologous MSCs were transplanted by means of intrarenal arterial injections to assess the adverse effects of cisplatin in two CKD models: preventative and stable. Preventative CKD monkeys (n = 3) underwent cell transplantation 4 days after the cisplatin injection. The stable CKD monkeys (n = 2) underwent cell transplantation 6 months after the cisplatin injection. Non-treated (n = 4) and normal saline-injected animals (n = 3) comprised the control and vehicle groups, respectively. We followed the animals for survival rate, serum biochemistry, urine analysis and histopathological indices. RESULTS: In the preventive CKD model, MSC transplantation tended to improve some renal functions but significantly reduced the histopathologic score compared with the vehicle and control groups. In the stable CKD model, MSCs did not ameliorate renal function or pathological score. CONCLUSIONS: These results suggest that MSCs tend to delay progression of CKD and fibrosis but do not reduce established interstitial fibrosis in this unique primate model of cisplatin-induced nephrotoxicity.

Association between hepcidin, haemoglobin level and iron status in stage 4 chronic kidney disease patients with anaemia.

OBJECTIVE: To explore the probable association of serum hepcidin and haemoglobin levels with iron and inflammation statuses in patients of chronic kidney disease stage 4 with anaemia. METHODS: The cross-sectional study was conducted at Tabriz University of Medical Sciences, Iran, from March 2011 to October 2012, and comprised patients of chronic kidney disease stage 4 with anaemia. Serum biochemical factors as well as hepcidin, ferritin, interleukin 6, high sensitivity C-reactive protein and iron levels were measured using standard methods. Statistical correlations were established using regression analysis and Pearson's correlation coefficient. RESULTS: There were 40 patients among whom 15(37.5%) were males and 25(62.5%) were females with an overall mean age of 55.68±14.4 years. There was a significant inverse relationship between hepcidin and haemoglobin levels (p<0.05). There were significant correlations between hepcidin with iron status, nutritional and inflammatory markers such as ferritin, Total iron binding capacity, albumin and interleukin 6 (p<0.05 each). CONCLUSIONS: Hepcidin had negative correlation with haemoglobin level in stage 4 chronic kidney disease patients with adequate iron stores, which could be effective in the development of anaemia in such patients.

Second and Third Kidney Transplants.

Renal transplant is the best procedure for patients with end-stage renal disease. Although an ideal kidney transplant should survive for the lifetime of each recipient, there may be a need for a second, third, or even a fourth retransplant. The outcomes of these kidney allografts, surgical approaches, immunology issues, and drug therapies warrant greater focus. Pediatric kidney retransplant is even more important because these patients are more immunologically responsive to donor antigens and because they need longer allograft survival. Although kidney retransplant provides a survival advantage for patients who would otherwise remain on the wait list and/or hemodialysis, careful patient selection is crucial for second, third, and fourth renal transplants. Despite the shortage of donor organs, outcomes, manageable complications, and economic considerations support earlier kidney retransplants rather than delayed retransplants. Preoperative vascular imaging, appropriate induction therapy, regular monitoring of renal function, and regular surveillance for malignancy and infection are more important in the retransplanted kidneys than in cases of first kidney transplants. The lack of robust data on optimal clinical management of these retransplant recipients has contributed to substantial variations in clinical practice among different centers. In this review, we discuss medical and surgical approaches in the cases of second and third kidney transplants.

The Effects of Remdesivir and Dexamethasone on Renal Sirtuin-1 Expression and Renal Function in Male Rats.

Remdesivir (REM) and dexamethasone (DEX) both have been used to treat coronavirus disease 2019 (COVID-19). The present study aimed to evaluate the effects of REM and DEX on kidney structure and function with particular focus on the probable renal sirtuin-1 (SIRT1) expression alteration in rats. Twenty-four male Wistar rats were divided into four groups, as follows: group A (control) received normal saline (5 mL/kg/day for 10 days); group B (REM) received REM (17 mg/kg/day on the first day, and 8.5 mg/kg/day on the 2nd-10th days); group C (REM + DEX) received both REM (17 mg/kg/day on the first day, and 8.5 mg/kg/day on the 2nd-10th days) and DEX (7 mg/kg/day, for 10 days); group D (DEX) received DEX (7 mg/kg/day for 10 days). Renal SIRT1 expression and kidney structure and function-related factors were evaluated by standard methods. The mean levels of urea in the REM + DEX group (60.83 ± 6.77, mg/dL) were significantly higher than in the control (48.33 ± 3.01, mg/dL; p = 0.002) and DEX (51.22 ± 4.99, mg/dL; p = 0.018) groups. The mean levels of creatinine in the REM (0.48 ± 0.08, mg/dL) and REM + DEX (0.50 ± 0.04, mg/dL) groups were higher than in the control group (48.33 ± 3.0 mg/dL) significantly (p = 0.022 and p = 0.010, respectively). The renal SIRT1 expression was significantly (p = 0.018) lower in the REM + DEX group (0.36 ± 0.35) than in the control group (1.34 ± 0.48). Tubulointerstitial damage (TID) scores in REM + DEX-treated rats (2.60 ± 0.24) were significantly higher than in the control (0.17 ± 0.17, p = 0.001) and DEX (0.50 ± 0.29, p = 0.005) groups. The administration of DEX and REM might lead to kidney injury associated with SIRT1 downregulation.

Effects of zinc supplementation on antioxidant status and lipid peroxidation in hemodialysis patients.

OBJECTIVES: This study was designed to determine the effects of zinc supplementation on oxidative stress in hemodialysis (HD) patients through evaluating total antioxidant capacity (TAC), whole blood glutathione peroxidase (GSH) level, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) level. DESIGN AND SETTING: Double-blinded randomized controlled trialfrom October 2006 to December 2007 at Tabriz Imam Khomeini Hospital. SUBJECTS: Sixty-five HD patients were randomly enrolled into 2 groups. INTERVENTION: Patients received placebo in group A and zinc (100 mg/day) in group B for 2 months. After a washout period for 2 months, the groups were crossed over and the study was continued for an additional 2 months. MAIN OUTCOME MEASURES: Serum zinc concentration was measured using atomic absorption spectrophotometry. TAC, GSH level, and SOD activity were determined by commercial enzyme-linked immunosorbent assay kits. MDA level was measured using a thiobarbituric acid method. RESULTS: The levels of serum zinc, TAC, GSH (P < .001 for all), and SOD activity (P < .001 for group A and P = .003 for group B) significantly increased after zinc supplementation whereas the serum level of MDA decreased after the same period (P = .003 for group A and P < .001 for group B). CONCLUSIONS: Zinc supplementation for 2 months improved the serum levels of zinc, antioxidant status, and lipid peroxidation in HD patients.

Protective effect of fish oil supplementation on DNA damage induced by cigarette smoking.

The study examined the influence of fish oil (FO) supplementation on serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels as indicated by DNA damage markers and total antioxidant capacity (TAC) among male cigarette smokers. This double-blind, placebo-controlled randomized study was conducted among healthy cigarette smokers (n=40) who were part of a larger prospective cohort study. Twenty smokers were randomly selected to receive FO for 3 months (1 g/day), and another 20 smokers received a placebo for 3 months; 8-OHdG and TAC levels were measured in blood samples before and after the intervention. Serum 8-OHdG significantly decreased (p=0.001) and TAC increased (p<0.001) after 3 months of treatment with FO. Between baseline and endline, the difference in 8-OHdG significantly correlated with the difference in TAC among smokers who received FO (r=-0.540, p=0.014). The study provides evidence that FO supplementation can modify decreased antioxidants and increased oxidative DNA damage in cigarette smokers.

Serum paraoxonase phenotype distribution in exudative age-related macular degeneration and its relationship to homocysteine and oxidized low-density lipoprotein.

PURPOSE: Disequilibrium between oxidative stress and antioxidant levels has been proposed as an important case of exudative age-related macular degeneration (AMD). The aim of the present study was to investigate homocysteine (Hcy) level and antioxidant paraoxonase 1 (PON1) activity within its phenotypes together with oxidized low-density lipoprotein (OX-LDL) levels in the patients with exudative AMD. METHODS: Serum PON1 activity and plasma Hcy and OX-LDL levels were analyzed in 45 exudative AMD patients and compared with 45 healthy controls. Paraoxonase 1 activity was measured in serum using paraoxon and phenylacetate as substrates. The PON1 phenotype was determined using double-substrate method. Homocysteine and OX-LDL levels were determined by enzyme-linked immunosorbent assay method. RESULTS: The distribution of PON1 phenotypes was significantly different between the patients with exudative AMD and control subjects (chi-square = 6.17, P = 0.01). AA phenotype with low activity was significantly more frequent in exudative AMD patients compared with healthy subjects (62.2% vs. 35.6%, respectively). Other phenotype frequencies in the patients compared with controls were as AB phenotype (intermediate activity) 28.9% versus 46.7% and BB phenotype (high activity) 8.9% versus 17.8%, respectively. Except in BB phenotype (P = 0.2), patients with AA and AB phenotypes had higher plasma Hcy levels in comparison to those of controls (P = 0.02 and P = 0.03, respectively). The mean OX-LDL levels, in all 3 phenotypes (P < 0.05), and OX-LDL/high-density lipoprotein ratio, in AA and AB phenotypes (P = 0.001, P = 0.1, respectively) but not in BB (P = 0.1), were significantly higher in the patients than controls. No significant differences in comparison of Hcy and OX-LDL levels between 3 PON1 phenotypes in both control (P = 0.6 for Hcy, P = 0.7 for OX-LDL) and patients (P = 0.8 for Hcy, P = 0.6 for OX-LDL) were found CONCLUSION: Increased plasma OX-LDL levels and ratios of OX-LDL/high-density lipoprotein, as biomarkers of lipoprotein oxidative stress, higher levels of Hcy, as oxidant agent, and more common low or intermediate PON1 activity in patients with exudative AMD, compared with controls, indicate that PON1 activity is insufficient to explain the increased oxidative stress observed in exudative AMD.

Paraoxonase enzyme activity is enhanced by zinc supplementation in hemodialysis patients.

BACKGROUND AND AIMS: Patients on maintenance hemodialysis (HD) face an increased risk of atherosclerosis, a crucial problem and the leading cause of cardiovascular morbidity and mortality. This study was designed to evaluate the effects of zinc supplementation on paraoxonase (PON) enzyme activity in patients on HD. METHODS: This double-blind randomized controlled trial was conducted from June 2005 to June 2007. Sixty HD patients were enrolled and divided into two groups: treatment (case) and control. The treatment and control groups were treated with 100 mg/day zinc or placebo, respectively, for 2 months. Serum zinc concentration was measured by atomic absorption spectrophotometry. PON activity was evaluated by spectrophotometric method. Lipid profile was determined using commercial kits, and apolipoprotein AI (Apo-AI) and B (Apo-B) levels were measured by commercial immunoturbidimetric kits. RESULTS: In the case group, there was no significant change in the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and Apo-B levels, while the serum levels of high-density lipoprotein (HDL), Apo-AI, and PON activity were significantly increased (p = 0.02). In the control group, although significant increases were observed in the serum levels of TC, TG, and Apo-B (p = 0.009, 0.019, and 0.001, respectively), the serum PON activity was significantly decreased (p = 0.025) and the serum levels of HDL, LDL, and Apo-AI were not changed. At the end of intervention period, the serum level of Apo-AI and PON activity were significantly higher in the case group. CONCLUSIONS: Zinc supplementation increased both the activity of PON and the serum level of Apo-AI in the HD patients.

Donation After Cardiac Death in Children.

The wait list for organ transplant exceeds the rate of organ donation, especially in children. The solid-organ transplant rate has remained stable over time, despite increased demand. Although donation after cardiac death has helped to expand the donor organ pool for the adult population, this option remains scarce for children in need of transplant. Because long-term graft survival is more important in the pediatric group than in adults, we should reconsider the common notion that donation after cardiac death is inferior to donation after brain death. Herein, we review the literature to extract and analyze data regarding donation after cardiac death for solid-organ transplant in children.

Expanded Criteria Donors.

The expanded criteria donor is any donor over the age of 60 years or a donor over the age of 50 years with 2 of the following 3 items: (1) history of high blood pressure, (2) serum creatinine ≥1.5 mg/dL, and (3) death due to stroke. To accept an expanded criteria donor kidney may significantly decrease the amount of time a person waits for transplant but requires written informed consent from the recipient. Although expanded criteria donor kidneys have predictably shorter outcomes than standard criteria donors, the exact risk is unknown. At 5 years follow-up, 50% of expanded criteria donor kidneys are still working. Regardless of donor status of these kidneys as expanded criteria or standard criteria, the transplant recipients have higher survival rates compared with candidates who remain on the wait list. The success rate may be increased when a perfusion pump is used to preserve the kidneys. Sometimes the function of a single kidney from an expanded criteria donor is deemed insufficient. In this situation, a pair of marginally functioning kidneys may be transplanted as a dual-kidney transplant. This dual transplant option offers acceptable outcomes as good as a single-kidney transplant with normal function and can effectively address the shortage of donor organs. The use of a perfusion pump allows the clinician to decide whether or not to use a particular expanded criteria donor kidney. Expanded criteria donors may be justified by meticulous selection of each donor for recipients, along with more sophisticated surgical techniques to maximize the kidney donor pool.

Effect of Lower- versus Higher-Intensity Isometric Handgrip Training in Adults with Hypertension: A Randomized Controlled Trial.

This study compared the effects of lower- versus higher-intensity isometric handgrip exercise on resting blood pressure (BP) and associated clinical markers in adults with hypertension. Thirty-nine males were randomly assigned to one of three groups, including isometric handgrip at 60% maximal voluntary contraction (IHG-60), isometric handgrip at 30% IHG-30, or a control group (CON) that had been instructed to continue with their current activities of daily living. The volume was equated between the exercise groups, with IHG-60 performing 8 × 30-s contractions and IHG-30 performing 4 × 2-min contractions. Training was performed three times per week for 8 weeks. Resting BP (median [IQR]), flow-mediated dilation, heart rate variability, and serum markers of inflammation and oxidative stress were measured pre- and post-intervention. Systolic BP was significantly reduced for IHG-60 (−15.5 mmHg [−18.75, −7.25]) and IHG-30 (−5.0 mmHg [−7.5, −3.5]) compared to CON (p < 0.01), but no differences were observed between both the exercise groups. A greater reduction in diastolic BP was observed for IHG-60 (−5.0 mmHg [−6.0, −4.25] compared to IHG-30 (−2.0 mmHg [−2.5, −2.0], p = 0.042), and for both exercise groups compared to CON (p < 0.05). Flow-mediated dilation increased for both exercise groups versus CON (p < 0.001). IHG-30 had greater reductions in interleukin-6 and tumor necrosis factor-α compared to the other groups (p < 0.05) and CON (p = 0.018), respectively. There was a reduction in Endothelin-1 for IHG-60 compared to CON (p = 0.018). Both the lower- and higher-intensity IHG training appear to be associated with reductions in resting BP and improvements in clinical markers of inflammation and oxidative stress.

Plasma oxidized LDL and thiol-containing molecules in patients with exudative age-related macular degeneration.

PURPOSE: It was proposed that total thiols (tSH) as powerful reducing agents and oxidized low-density lipoprotein (OX-LDL) may be associated with development of choroidal neovascularization in exudative age-related macular degeneration (E-ARMD). METHODS: In a case-control study, 45 patients with E-ARMD were compared with 45 sex- and age-matched healthy controls. The levels of plasma homocysteine (Hcy) and OX-LDL as oxidant agents, and of tSH and glutathione (GSH) as antioxidant markers, were estimated in E-ARMD patients and controls. RESULTS: The levels of Hcy (15.4±7.2 µM versus 10.7±3.7 µM; p=0.001) and OX-LDL (52.2±13.8 U/l versus 37.8±10.8 U/l; p=0.001) were statistically higher, while GSH (1.10±0.97 µM versus 2.09±1.04 µM; p=0.001) and tSH (0.31±0.06 mM versus 0.35±0.05 mM; p=0.001) were statistically lower, in the patients with E-ARMD than in the control group, respectively. The plasma OX-LDL concentration also exhibited a positive and significant correlation with Hcy (r=0.719, p=0.001) in patients with E-ARMD. CONCLUSIONS: Lower GSH and tSH as antioxidant and higher Hcy levels as oxidant agents in E-ARMD patients may have resulted in an oxidative environment that was associated with OX-LDL. Further studies with more cases are required to confirm the hypothesis.

New Markers for Transplant Rejection.

Monitoring allograft function after kidney transplant has routinely relied on the use of nonspecific markers, such as serum creatinine, glomerular filtration rate, proteinuria, and donor-specific antibodies. These traditional markers have low sensitivity and fail to detect subclinical changes. Diagnosis of renal allograft dysfunction still requires an allograft biopsy, as it remains the criterion standard for assessment of graft status. However, renal biopsy is an invasive procedure, and sampling errors may result in misdiagnosis, perhaps causing graft failure. New biomarkers have been developed to monitor allograft function, although many are not yet routinely used. Other shortcomings, such as lack of standardization and high cost, should be solved before their widespread application in the clinic. A recipient's immune status could be monitored by use of urine or blood samples. These include functional cell-based assays and the evaluation of molecular expression at the messenger RNA or protein levels. Molecular technologies, including molecular microscope diagnostic systems, have been recently developed to improve the yield of histologic evaluation of the allograft biopsy. Prospective, interventional trials are required to demonstrate whether these new biomarkers improve patient or transplant outcomes. Implementation of these technologies into standard clinical practice remains challenging until their generalizability, cost, ease of interpretation, and the identification of patients who may benefit from more than standard-of-care surveillance can be determined. These biomarkers could allow immunosuppressive therapy to be individualized for patients.

DIBc nano metal-organic framework improves biochemical and pathological parameters of experimental chronic kidney disease.

BACKGROUND: The growing morbidity and mortality rate of chronic kidney disease (CKD) has forced researchers to find more efficient strategies for controlling this disease. Studies have proven the important role of alteration in iron, zinc and selenium metabolism in CKD pathological process. Nanotechnology, through synthetizing nano metal-organic framework (NMOF) structures, can be employed as a valuable strategy for using these trace elements as the key for modification and improvement of CKD-related pathological events. After proving the anti-diabetic property of DIBc NMOF (which contains selenium and zinc) in the previous study, the impact of this NMOF on some important biochemical and pathological parameters of CKD was evaluated in the current study. METHODS: Knowing that diabetic nephropathy (DN) is the leading cause of CKD, male wistar rats were selected and given a high fat diet for 2 weeks and then were injected with streptozotocin (35 mg/kg) to induce DN. Six weeks after streptozotocin injection, DIBc or metformin treatment started and continued for 8 weeks. RESULTS: Eight weeks of DIBc treatment decreased plasma fasting blood glucose, blood urea nitrogen, uric acid, malondialdehyde (MDA) and HOMA-IR index compared to DN control and metformin groups. This NMOF significantly reduced urinary albumin excretion rate, MDA and 8-isoprostane, while it increased creatinine clearance in comparison to the above-mentioned groups. Renal histo-pathological images indicated that DIBc ameliorated glomerular basement membrane thickening and wrinkling, mesangial matrix expansion and hypercellularity and presence of intra-cytoplasmic hyaline droplets in proximal cortical tubules of kidney samples. CONCLUSION: The results showed the therapeutic effect of DIBc on important biochemical and histo-pathological parameters of CKD, so this NMOF could be regarded as a promising novel anti-CKD agent.

BCc1 Nanomedicine Therapeutic Effects in Streptozotocin and High-Fat Diet Induced Diabetic Kidney Disease.

BACKGROUND: One common feature of chronic diseases, such as cancer, diabetes and chronic kidney disease (CKD), is the disruption of iron metabolism and increase in labile iron pool, which can result in excessive production of harmful oxidative stress. The proper management of iron metabolism in this situation can be a valuable tool to ameliorate pathological events. MATERIALS AND METHODS: In the previous studies, the anti-neoplastic effects of BCc1, a nanochelating-based nanomedicine with iron-chelating property, were demonstrated in cell culture, animal models and clinical trials. In the present study, the therapeutic effects of BCc1 in animal model of diabetic kidney disease (DKD), induced by streptozotocin injection (35 mg/kg) and high-fat diet consumption, were evaluated. RESULTS: The results showed that BCc1 significantly decreased HOMA-IR index, uric acid, blood urea nitrogen, malondialdehyde and 8-isoprostane. In addition, it reduced urinary albumin excretion rate and albumin-to-creatinine ratio in comparison to DKD control rats. This nanomedicine had no negative impact on liver iron content, hemoglobin level, red blood cell count, hematocrit and mean corpuscular volume, while it significantly decreased aspartate aminotransferase and alanine aminotransferase compared to DKD control group. Moreover, the histopathological assessment indicated that lesser glomerular basement membrane and wrinkling, mesangial matrix expansion and pathological changes in proximal cortical tubules were seen in the kidney samples of BCc1-treated rats. CONCLUSION: In conclusion, BCc1 as an iron-chelating agent shows promising impacts in DKD animal model, which can ameliorate biochemical and pathological events of this disease.