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- Renal tight junction proteins are decreased in cisplatin-induced nephrotoxicity in rats. [JOURNAL ARTICLE]
- Toxicol Mech Methods 2014 Jul 23.:1-31.
Abstract Cisplatin (CP) is an antineoplasic agent that induces nephrotoxicity and oxidative stress. It is unknown whether renal tight junction (TJ) proteins expression and localization are modified in CP-induced nephrotoxicity. Objective: To study if the expression of the TJ proteins occludin, claudin-2, claudin-5 and zonula occludens-1 (ZO-1) is modified in rats with CP-induced nephrotoxicity. Materials and methods: Male Wistar rats (n=5/group) were injected with saline solution (V group) and the other group (CP group) was injected with a single dose of saline solution and CP (7.5 mg/kg i.p.). Rats were sacrificed 72 h after CP injection and blood and 24-h urine samples were collected. Several plasma and urinary injury biomarkers as well as renal histopathology lesions, oxidative and nitrosative stress markers were evaluated and protein levels of ocludin, claudin-2, claudin-5, ZO-1 were measured by Western blot. Statistically significant changes noted with different p<0.05 versus V. Results: nephrotoxicity was evident by histological alterations, glycosuria, decrease in creatinine clearance, and increase in fractional excretion of sodium, serum creatinine and kidney injury molecule-1. These changes were associated with oxidative/nitrosative stress (increased renal abundance of 3-nitrotyrosine and protein kinase C β2 and decreased renal expression of nuclear factor-erythroid-2-related factor 2) and decreased activity of antioxidant enzymes. Finally, it was found that CP induced renal damage was associated with decreased renal expression of occludin and claudin-2. Discussion and conclusion: CP altered the TJ proteins expression and localization in the proximal tubule that was associated with oxidative/nitrosative stress.
- SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. [JOURNAL ARTICLE]
- Biopharm Drug Dispos 2014 Jul 7.
Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, we analyzed SUA and the urinary excretion rate of UA (UEUA ) after the oral administration of luseogliflozin, an SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA , suggesting that SUA decreased as a result of the increase in the UEUA . The increase in UEUA was correlated with an increase in urinary D-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, we focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and D-glucose. We observed that the efflux of [(14) C]UA in Xenopus oocytes expressing GLUT9 isoform 2 was trans-stimulated by 10 mM D-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, uptake of [(14) C]UA by oocytes was cis-inhibited by 100 mM D-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could be potentially increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. This article is protected by copyright. All rights reserved.
- New Treatments for Type 2 Diabetes: Cardiovascular Protection Beyond Glucose Lowering? [REVIEW]
- Heart Lung Circ 2014 Jun 10.
The health burden of type 2 diabetes mellitus (T2DM) is increasing worldwide, with a substantial portion of this burden being due to the development of cardiovascular (CV) disease. Multiple individual randomised clinical trials of intensive versus conventional glucose control, based on the use of traditional oral hypoglycaemic agents, have failed to convincingly show that intensive glucose control significantly reduces CV disease outcomes. In recent times, two new approaches to lowering glucose levels have become available. One targets the "incretin effect" which involves the modulation of peptide hormones that normally regulate glucose levels when nutrients are given orally. The other approach is based on inhibiting the sodium-glucose co-transporter 2 (SGLT-2) in the tubules of the kidney to promote glycosuria. Incretin-based therapies, especially glucagon-like peptide-1 receptor analogues, reduce glucose levels, with a low risk of hypoglycaemia, by increasing insulin secretion, inhibiting glucagon release and increasing satiety. Clinical and experimental studies have also shown favourable effects on CV disease risk factors such as dyslipidaemia, blood pressure, and improvements in endothelial function and cardiac contractility. Similarly, SGLT-2 inhibitors reduce glucose levels with a low risk for hypoglycaemia and have positive effects on multiple CV disease risk factors. Whether the beneficial effects of these new glucose lowering approaches on surrogate markers of CV disease risk translates to an improvement in CV events remains unknown. Several CV outcome trials are currently being performed to show that at a minimum, these novel glucose lowering agents are safe, but also have positive CV benefits.
- Supplemental iron intake and the risk of glucose intolerance in pregnancy: re-analysis of a randomised controlled trial in Finland. [JOURNAL ARTICLE]
- Matern Child Nutr 2014 Jul 4.
Observational studies suggest that high iron intake during pregnancy is associated with the risk of gestational diabetes. As such studies are prone to bias, we re-analysed data from a randomised controlled trial of iron supplementation to see whether it supports the risk found in observational studies. The trial was conducted in primary health care setting in five municipalities in Finland in 1985-1986. The participants were 2944 women (95% of pregnant women in the area) who were randomly allocated either to (1) the selective iron group (elemental iron 50 mg twice a day only if diagnosed as anaemic, continuing until their haemoglobin increased to 110 g L(-1) ) or (2) the routine iron group (elemental iron 100 mg day(-1) throughout the pregnancy regardless of haemoglobin level). The numbers of women in the analyses were 1358 and 1336, respectively. The main outcome measure was a composite variable including any glucose intolerance-related outcome (e.g. glucosuria, gestational diabetes, large-for-gestational-age child) in mothers' or children's patient records during pregnancy and post-partum. There were no statistically significant differences in the incidence of the primary outcome between the selective iron and the routine iron groups (13.0 vs. 11.0%, P = 0.12). The most common outcome was large-for-gestational-age calculated from children's hospital data (8.3 vs. 8.2%, P = 0.95). The results were mainly similar when stratified by the mothers' baseline haemoglobin level, body mass index or gestational weight gain. Routine iron supplementation throughout pregnancy did not increase the risk of glucose intolerance during pregnancy. The results need to be confirmed in future trials.
- Hypokalaemic paralysis and normocalcaemic tetany--a rare presentation of Sjogren's syndrome. [Journal Article]
- J Assoc Physicians India 2013 Nov; 61(11):818-20.
38 year old woman was admitted with acute onset of quadriplegia. Biochemical investigation revealed severe hypokalaemia with hyperchloraemic metabolic acidosis, alkaline urine, and positive urinary anion gap which are the hallmark of distal tubular acidosis. In addition she also had hypophosphataemia, normoglycaemic glycosuria, aminoaciduria, and hyperphosphaturia suggestive of proximal tubular dysfunction. Further evaluation confirmed the diagnosis of Sjogren's syndrome. Interestingly our patient also had carpopedal spasm despite normal calcium and magnesium level. Quadriplegia and carpopedal spasm improved with correction of hypokalaemia and acidosis. Proximal tubular abnormalities (except albuminuria) were normalised at the time of discharge. Distal tubular acidosis is a well known renal manifestation of Sjogren's syndrome. But this type of transient proximal tubular dysfunction with distal tubular acidosis in Sjogren's syndrome is very rare and hypokalaemic tetany also deserves mention.
- Sodium-Glucose Linked Transporter 2 (SGLT2) Inhibitors-Fighting Diabetes from a New Perspective. [JOURNAL ARTICLE]
- Adv Ther 2014 Jun 28.
Sodium-Glucose linked transporter 2 (SGLT2) inhibitors are a new family of antidiabetic pharmaceutical agents whose action is based on the inhibition of the glucose reabsorption pathway, resulting in glucosuria and a consequent reduction of the blood glucose levels, in patients with type 2 diabetes mellitus. Apart from lowering both fasting and postprandial blood glucose levels, without causing hypoglycemia, SGLT2 inhibitors have also shown a reduction in body weight and the systolic blood pressure. This review paper explores the renal involvement in glucose homeostasis providing also the latest safety and efficacy data for the European Medicines Agency and U.S. Food and Drug Administration approved SGLT2 inhibitors, looking, finally, into the future of this novel antidiabetic category of pharmaceutical agents.
- Assessment of glycaemic control in patients with diabetes mellitus on insulin therapy. [Journal Article]
- J Indian Med Assoc 2013 Nov; 111(11):761-5.
- The problem of renal function monitoring in patients treated with the novel antiretroviral drugs. [Journal Article]
- HIV Clin Trials 2014 May-Jun; 15(3):87-91.
Chronic kidney disease (CKD) is currently considered a major comorbidity in patients affected by HIV infection. In addition, new generation antiretroviral drugs that interact with creatinine transporters were recently introduced. Rilpivirine, dolutegravir, and cobicistat, with different mechanisms, inhibit the amount of tubular secretion of creatinine causing a slight increase in serum creatinine levels and consensual eGFRcreat reduction. This will require an unprecedented attention to renal issues, because the new drugs can also be associated to old antiretroviral drugs that may exert renal toxic effects. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimating GFR would be desirable. At the moment, methods of direct GFR measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate GFR is still recommended, considering the apparent reduction of eGFRcreat due to these drugs. Tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid. More specific and sensitive markers of tubular damage are still not readily available in all clinical labs. HIV patients treated by the novel drugs need to be monitored on a monthly basis for the first 3 months. Subsequent monitoring should be performed on a quarterly basis or guided by comorbidities.
- The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. [JOURNAL ARTICLE]
- Am J Physiol Renal Physiol 2014 Jun 18.
Diabetic nephropathy is the leading cause of end-stage renal disease in man in the western world. Recent development of sodium-glucose co-transporter 2 (SGLT2) inhibitors offers a new anti-diabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on developing type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR ob/ob mice, which spontaneously develop type 2 diabetic nephropathy. In a first experiment, BTBR ob/ob mice either received a diet containing 300ppm empagliflozin or equicaloric placebo chow for 12 weeks. In a second experiment, BTBR ob/ob mice received 1µg/kg body weight/d angiotensin II to induce arterial hypertension and were separated in the same 2 diet groups for 6 weeks. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, as well as mesangial matrix expansion only in BTBR ob/ob mice without hypertension. In summary, empagliflozin demonstrated significant anti-hyperglycemic effects differentially ameliorating early features of diabetic nephropathy in BTBR ob/ob mice with and without hypertension.