sildenafil-citrate and Diabetic-Nephropathies

The present study aimed to investigate the effect of nano selenium, sildenafil, and their combination on inflammation, oxidative stress, and apoptosis in streptozotocin-induced diabetic nephropathy in rats. Herein, a new anti-inflammatory pathway for sildenafil as a high-mobility group box (HMGB1) inhibitor was proposed using the molecular docking technique.. Rats were divided into 7 groups: normal control, control nano selenium, control sildenafil, control diabetic, diabetic+ nano selenium, diabetic+ sildenafil, diabetic+ nano selenium+ sildenafil. The effects of drugs were evaluated by measuring serum urea, creatinine, lactate dehydrogenase (LDH), levels of tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1β), HMGB1, receptor advanced glycation end product (RAGE), malondialdehyde (MDA), thioredoxin reductase (TrxR) by biochemical assays, nuclear factor-kappa b (NF-κB), toll-like receptor (TLR4) by immunohistochemistry, gene expressions of caspase 3 and monocyte chemoattractant protein (MCP-1) besides histopathological investigations of renal cells.. Results showed beneficial effects of 8 weeks of treatment by nano selenium and sildenafil supported by improvement in kidney function, histopathological changes, and reduction in all of these parameters. These results supported molecular docking that indicated sildenafil had a high binding score and interactions with the HMGB1 receptor.. The current study demonstrated a renoprotective effect of nano‑selenium and sildenafil by interfering at multiple pathways, especially the HMGB1/NF-κB signaling pathway.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; HMGB1 Protein; Kidney; Molecular Docking Simulation; NF-kappa B; Oxidative Stress; Rats; Selenium; Sildenafil Citrate; Streptozocin

The goal of this study was to investigate the effect of different phosphodiesterase inhibitors (PDEIs), on renal oxidant/antioxidant balance in diabetic rats. Our study was conducted on 125 rats, diabetes was induced in 100 rats by a single administration of streptozocin (STZ). Diabetic rats were divided into four equal groups. The first group was assigned as diabetic control, the remaining three groups were treated with pentoxifylline, sildenafil and milrinone via drinking water for 15 successive days, another group of 25 normal rats was assigned as non-diabetic control. Significant increase in plasma levels of glucose, urea, creatinine, malondialdehyde (MDA), and nitric oxide (NO) with a concomitant decrease in the levels of insulin, reduced glutathione (GSH), glutathione peroxidase (Gpx), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC) were observed in diabetic rats. These alterations were reverted back to near normal level after treatment with PDEIs. Our data seem to suggest a potential role of PDEIs in maintaining health in diabetes by reducing the progression of diabetic nephropathy.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Kidney; Lipid Peroxidation; Male; Milrinone; Oxidative Stress; Oxidoreductases; Pentoxifylline; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Random Allocation; Rats, Sprague-Dawley; Renal Insufficiency; Sildenafil Citrate

The present study evaluates the possible mechanism of sildenafil citrate (SIL) for the attenuation of renal failure in diabetic nephropathic (DN) animals.. Diabetic nephropathy was induced by a single dose of streptozotocin (STZ) (60 mg/kg, i.p.) and confirmed by assessing the blood and urine biochemical parameters on the 28th day of its induction. The selected DN animals were treated with glimepiride (0.5 mg/kg, p.o.) and SIL (2.5 mg/kg, p.o.) for a period of 6 weeks. Biochemical parameters in blood and urine were estimated after the 29th and 70th day of the protocol for the estimation of the effect of SIL.. There were significant alterations in the blood and urine biochemical parameters in STZ-treated groups which confirmed DN. There was a significant decrease in the triglyceride level in the SIL-only-treated group on the 70th day of the protocol. The histopathology study also suggested that SIL treatment results in the improvement in the podocyte count in DN animals.. The present study concludes that SIL improves the renal function by decreasing the triglyceride level and improving the podocyte count in DN animals.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney Function Tests; Male; Phosphodiesterase 5 Inhibitors; Podocytes; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Streptozocin; Sulfonylurea Compounds; Triglycerides

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the world. Several signaling pathways are involved in the pathogenesis of DN including elevation in level of angiotensin II, formation of advanced glycation end products (AGE), activation of protein kinase c (PKC), and lipid accumulation. These pathways activate one another mutually leading to oxidative stress, increasing expression of transforming growth factor beta-1(TGF-β 1) and release of interleukins and adhesion molecules, so the aim of this study is to interrupt more than pathogenic pathway to ameliorate the progression of DN. In the present study, white male rats (N=48) were divided into six groups (8 rats each), the first two groups served as normal control and a control vehicle group while the remaining four groups were rendered diabetic by a single intraperitoneal injection of Streptozotocin (STZ) and being left for 4 weeks to develop DN. Thereafter, the rats were divided into DN group, DN group receiving Telmisartan or Sildenafil or Telmisartan Sildenafil combination. After the specified treatment period, urine samples were collected (using metabolic cages) to measure proteinuria, animals were then euthanized, blood and tissue samples were collected for measurement of Blood glucose,BUN, S.Cr, LDL, NO, TGF-β1, IL-1β, AGEPs, and SOD. The combination therapy showed significant decrease in BUN, S.Cr,LDL, TGF-β1, IL-1β, Proteinuria and AGEPs and significant increase in SOD and NO. The findings showed that combination therapy was able to ameliorate DN and that the effects were superior to the single drugs alone.

Topics: Animals; Benzimidazoles; Benzoates; Blood Glucose; Blood Urea Nitrogen; Body Weight; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Glycation End Products, Advanced; Interleukin-1beta; Kidney; Nitric Oxide; Proteinuria; Rats; Sildenafil Citrate; Streptozocin; Superoxide Dismutase; Telmisartan; Transforming Growth Factor beta1

The present study evaluates possible drug interactions between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ)-induced diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction based on molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg kg(-1), i.p.) and was confirmed by assessing blood and urine biochemical parameters 28 days after induction. Selected DN animals were used to explore the drug interaction between GLIM (0.5 mg kg(-1), p.o.) and SIL (2.5 mg kg(-1), p.o.) on the 29th and 70th day of the protocol. Possible drug interaction was assessed by evaluating the plasma drug concentration using HPLC-UV and changes in biochemical parameters in blood and urine were also determined. The mechanism of the interaction was postulated from the results of a molecular modeling study using the Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in blood and urine biochemical parameters in STZ-treated groups. The concentration of SIL increased significantly (P < 0.001) in rat plasma when co-administered with GLIM on the 70th day of the protocol. Molecular modeling revealed important interactions with rat serum albumin and CYP2C9. GLIM has a strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL, whereas for CYP2C9, GLIM forms a stronger hydrogen bond than SIL with polar contacts and hydrophobic interactions. The present study concludes that bioavailability of SIL increases when co-administered chronically with GLIM in the management of DN animals, and the mechanism is supported by molecular modeling studies.

Topics: Animals; Blood Glucose; Cytochrome P-450 CYP2C9; Diabetic Nephropathies; Disease Models, Animal; Drug Interactions; Hypoglycemic Agents; Kidney Function Tests; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Phosphodiesterase 5 Inhibitors; Protein Conformation; Rats; Serum Albumin; Sildenafil Citrate; Structure-Activity Relationship; Sulfonylurea Compounds

It is well established that the pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide (NO) generation. Many of the biological actions of NO are mediated by cGMP, which is rapidly degraded by phosphodiesterases. In this study, we evaluated the renoprotective effects of sildenafil (SIL), an inhibitor of phosphodiesterase-5, in type 2 diabetic rats.. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetes model, and Long-Evans Tokushima Otsuka rats, a non-diabetic control, were treated with either SIL (2.5 mg·kg(-1) in drinking water) or undosed water for 28 weeks, starting at 30 weeks of age.. Sildenafil treatment significantly decreased albuminuria, attenuated glomerular hyperfiltration and resulted in a decrease in glomerular hypertrophy, in addition to a reduced glomerulosclerosis score and a dramatic decrease in the number of glomerular and tubulointerstitial proliferating cell nuclear antigen-positive cells in OLETF rats. This was accompanied by a significant reduction in renal cortical mRNA levels of collagen types I and III. The increased mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 in the OLETF rats were significantly or partially attenuated by SIL treatment.. This study suggests that SIL attenuated diabetic nephropathy due to its potent antiproliferative effects and its regulatory effects on extracellular matrix. This latter effect is thought to be a result of its ability to affect the balance between MMPs and their inhibitors.

Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Cell Proliferation; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney; Kidney Function Tests; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Inbred OLETF; Sildenafil Citrate; Sulfones; Transforming Growth Factor beta1

Oxidative stress and inflammation are implicated in the pathogenesis of diabetic nephropathy. Because sildenafil citrate (Viagra) has variable cardiovascular benefits, including antioxidative and immunomodulating effects, we investigated its influence on oxidative stress and inflammation in diabetic rat kidney.. Streptozotocin-induced diabetic rats received sildenafil (3 mg/kg/day in drinking water) or not (undosed water) for 8 weeks and were compared to age-matched nondiabetic animals. We evaluated 8-hydroxydeoxyguanosine (8-OHdG; for oxidative DNA damage), inducible nitric oxide synthase (iNOS) and nitrotyrosine (for excessive NO production and peroxynitrite formation), and representative chemoattractants [monocyte chemotactic protein-1, MCP-1; for inflammation and monocyte/macrophage infiltrations (ED-1)] in the kidney.. Sildenafil-treated rats had a lower kidney-to-body weight ratio than untreated diabetic rats. Urinary albumin excretion in diabetic rats decreased significantly after sildenafil treatment without changes in systolic blood pressure. Sildenafil-treated rats had significantly lower urinary and renal cortical 8-OHdG levels than the nonsildenafil group. Sildenafil administration significantly attenuated the increased renal nitrotyrosine protein expression, positive iNOS and ED-1 staining in glomeruli and tubulointerstitium, and nitrotyrosine staining in tubulointerstitium. Cortical MCP-1 RNA expression in the sildenafil group was significantly lower than in the nonsildenafil group.. Sildenafil treatment may attenuate renal damage by ameliorating oxidative and inflammatory injuries in diabetic rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Blotting, Western; Chemokine CCL2; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Immunohistochemistry; Inflammation Mediators; Kidney; Male; Nephritis; Nitric Oxide Synthase Type II; Oxidative Stress; Piperazines; Purines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sildenafil Citrate; Streptozocin; Sulfones; Tyrosine; Vasodilator Agents

Erectile dysfunction (ED) is common among patients on dialysis therapy. In the present study, we attempted administration of sildenafil to Japanese patients undergoing dialysis. In order to diagnose ED before prescribing sildenafil, we assessed the hemodialysis patients who desired sildenafil by using the five items version of the International Index of Erectile Function (IIEF-5). In addition, the characteristics of the quality of life in Japanese hemodialysis patients who desired sildenafil were assessed using the kidney disease quality of life (KDQOL). To all 37 male subjects (mean age of 53.8 +/- 10.4 years) attending the Outpatient Hemodialysis Unit at Atsugi Clinic (Atsugi City, Japan), it was explained by their primary doctor that the treatment of ED with sildenafil was possible. As a result, 10 patients (27.0%) desired the treatment. For eight patients, ED was diagnosed by IIEF-5 prior to prescription of sildenafil. The mean IIEF-5 scores were 6.13 +/- 4.67 points. Sildenafil was prescribed to five patients (three diabetic, two non-diabetic) and sexual function was improved in three cases. The main adverse effect was found to be ventricular arrhythmia in one case. As for KDQOL, the group desiring sildenafil showed significantly high values in Dialysis Staff Encouragement and Patient Satisfaction. Among the other nine dialysis patients (five diabetic, four non-diabetic; mean age of 58.1 +/- 8.9 years) who visited the ED department of Ishida Hospital (Asahikawa City, Japan), sildenafil was effective for all non-diabetic patients (100%) and for only one diabetic patient (20%). Among all 14 patients at Atsugi Clinic and Ishida Hospital, sildenafil efficacy rates were 83.3% for non-diabetic patients and 37.5% for diabetic patients. Non-diabetic patients without the side-effects were all responders for the sildenafil treatment. The patients who relied on the dialysis staff and were more satisfied with the general treatment in the dialysis institute desired the administration of sildenafil under the present circumstances wherein the dialysis population had few experiences of sildenafil treatment. Diabetic status is thought to be a negative factor for the response of sildenafil treatment in dialysis patients.

Topics: Aged; Comorbidity; Diabetic Nephropathies; Erectile Dysfunction; Health Status Indicators; Humans; Kidney Failure, Chronic; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Quality of Life; Renal Dialysis; Sildenafil Citrate; Sulfones