Does combined peroxisome proliferator-activated receptors-agonist and pravastatin therapy attenuate the onset of diabetes-induced experimental nephropathy?

To investigate the combined effects of rosiglitazone and pravastatin on renal functions in early streptozotocin induced diabetic nephropathy [DN]. This study was carried out at King Khalid University Hospital Animal House, Riyadh, Saudi Arabia from August 2013 to February 2014. Fifty male Wistar rats were assigned to normal control rats and diabetic rats that received saline, rosiglitazone, pravastatin, or rosiglitazone+pravastatin for 2 months. Their weight range was 230-250 gm, and age range was from 18-20 weeks. At the end of experiment, creatinine clearance, and urinary albumin to creatinine ratio [ACR] were measured. Blood samples were analyzed for transferrin, glycosylated hemoglobin [HbA1c], lipid profile, tumor necrosis factor-alpha [TNF-alpha], intercellular adhesion molecule-1 [ICAM-1], and lipid peroxide. Rosiglitazone treatment increased creatinine clearance and plasma transferrin, and decreased urinary ACR, HbA1c, plasma TNF- alpha, ICAM-1, and serum lipid peroxide levels without affecting the altered lipid profile. Pravastatin treatment produced similar results and normalized the lipid alteration. The combination of rosiglitazone and pravastatin was more effective in attenuating the diabetes-induced nephropathy compared with treatment with either drug alone. The combination strategy of rosiglitazone and pravastatin may provide a potential synergistic renoprotective effect against DN by improving renal functions and reducing indices of DN

potential role of anti tumor necrosis factor-alpha antibodies on some renal functions and vasoregulatory factors in preeclamptic pregnant Wistar rats

To investigate the potential role of anti-tumor necrosis factor-alpha [TNF-alpha] antibodies on some renal functions and release of vasoregulatory peptides using nitric oxide synthase deprived pregnant rats. This study was carried out at King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia from December 2011 to November 2012. Forty female Wistar rats were divided into 4 groups [10 rats each]; Group I - included virgin non-pregnant rats. Group II - included pregnant rats that received saline, Group III - received N[G]-nitro-L-arginine methyl ester [L-NAME], and Group IV -received both L-NAME and anti TNF- alpha antibodies. Mean arterial blood pressure, urine volume, creatinine clearance and 24 hours urinary albumin excretion were measured on day 20 of gestation. Blood samples were taken on day 20 of gestation for measurement of plasma endothelin-1 [ET-1], angiotensin II [Ag II] and serum levels of total nitric oxide [NO] products, interleukin-6 [IL-6] and soluble vascular cell adhesion molecule [sVCAM-1]. Viable pups were also weighed. Anti TNF- alpha antibodies reversed hypertension, improved renal function, decreased release of vasoactive substances and increased pup weight. Preeclampsia is associated with disturbed renal function, overproduction of cytokines and vasoregulatory factors, and fetal growth restriction. Treatment of pregnant rats with anti TNF- alpha antibodies, restored urine volume, creatinine clearance, plasma ET-1, serum IL-6 and sVCAM-1 to normal levels. Hence, anti TNF- alpha antibodies may have beneficial effects in preeclampsia. Additional studies are warranted to confirm these results

Effects of pravastatin or 12/15 lipoxygenase pathway inhibitors on indices of diabetic nephropathy in an experimental model of diabetic renal disease

To attenuate the effects of early streptozotocin-induced diabetes on renal functions through supplementation with either pravastatin or 12/15-lipoxygenase pathway inhibitors.The study was carried out at King Khalid University Hospital, Riyadh, Saudi Arabia from November 2010 to November 2011. Rats were assigned to control rats [group I] receiving vehicle; normoalbuminuric diabetic rats receiving vehicle [group IIa], nordihydroguaiaretic acid [NDGA] [group IIb], NDGA + insulin [group IIc], pravastatin [group IId] or pravastatin + insulin [group IIe]; and microalbuminuric diabetic rats receiving vehicle [group IIIa], NDGA [group IIIb], NDGA + insulin [group IIIc], pravastatin [group IIId] or pravastatin + insulin [group IIIe]. The NDGA and pravastatin were administered for 4 months. At the end of the experiment, renal function tests were measured and blood samples were analyzed. Both NDGA and pravastatin had favorable effects on renal function to the same extent, and more favorable effects when diabetes was controlled. Indices of diabetic nephropathy [DN] and oxidative stress were reduced by NDGA or pravastatin therapy with no statistical difference between the 2 lines of therapy. Pravastatin and 12/15-lipoxygenase pathway inhibitor [NDGA] have beneficial effects on streptozotocin-induced DN. The findings may provide insight into the feasibility of their clinical use as a complementary therapy for the prevention/treatment of DN.

Effects of adrenomedullin on some vasoregulatory factors in hypertensive pregnant rats as an animal model of preeclampsia

The aim of this study was to investigate the effects of adrenomedullin [ADM] on plasma renin activity and the release of vasoregulatory peptides as endothelin-1 [ET-1], nitric oxide [NO] and norepinephrine in nitric oxide synthase [NOSG] deprived pregnant rats as an animal model of preeclampsia using N -nitro-L-arginine methyl ester [L-NAME], a NOS inhibitor. Also the aim was to elucidate the possible beneficial effects of ADM on regulation of renal function, blood pressure, blood supply to uteroplacental unit and consequently on fetal growth. The current study was carried out on 60 female Wistar rats. Their average weight was 250-300 g. They were 13-18 weeks old. Two or three cycling female rats were housed with a male for 24 hours. The presence of sperms in vaginal smears was considered as day 1 of pregnancy. Rats were divided into four groups [15 rats each] according to the following experimental design: group I included virgin non-pregnant rats, group II included pregnant rats that received saline solution starting from day 7 to day 20 of gestation, group III included pregnant rats that were treated with L-NAME daily starting from the same day of gestation and for the same duration as for group II, to make an animal model of preeclampsia, group IV included pregnant rats that were treated by both L-NAME [the same dose and for the same duration as for group III] and recombinant rat ADM, 3 times a day starting from day 14 to day 20 of gestation. The following parameters were measured in the control and all pregnant rats on day 13 of gestation and also on day 20 of gestation: - mean arterial blood pressure [MAP], some renal function tests [including urine volume, urinary Na[+] and K[+], creatinine clearance as a measure of glomerular filtration rate [GFR], 24 h urinary albumin excretion], pup weight, plasma levels of ADM, endothelin-1 [ET-I], norepinephrin, total nitric oxide [NO] products and plasma renin activity [PRA]. L-NAME treatment of pregnant rats [group III] starting from day 7 to day 20 of gestation produced significant reduction of urine volume, creatinine clearance and total plasma NO as compared to control and normal pregnant rats [group II]. Moreover, their pup weight on day 20 of gestation was significantly reduced as compared to that of normal pregnant rats [P< 0.0001]. On contrast L-NAME treated rats on days 13 and 20 of gestation had significant increase of MAP, 24 h urinary Na and albumin excretion, plasma levels of ADM, ET-1, norepinephrin and PRA as compared to controls and group II on corresponding days of gestation where P<0.0001. ADM treatment of pregnant rats for 7 days starting from day 14 to day 20 of gestation significantly increased urine volume, urinary Na[+] excretion, creatinine clearance, plasma levels of ADM and total plasma NO products as compared to the same group on day 13 of gestation and L-NAME treated rats on days 13 and 20 of gestation. Moreover, their pup weight was significantly increased as compared to that of L-NAME treated rats on day 20 of gestation. However, no significant changes were detected as regard urinary K[+] excretion and PRA when comparing them to the same group on day 13 of gestation and L-NAME treated rats on days 13 and 20 of gestation. Also no significant change in plasma norepinephrin was detected between ADM and L-NAME treated rats on day 20 of gestation. On the other hand, MAP, 24 h urinary albumin excretion and plasma ET-1 level were significantly decreased in ADM treated rats on day 20 of gestation as compared to the same group on day 13 and L-NAME treated rats on days 13 and 20 of gestation. Comparing ADM treated pregnant rats on day 20 of gestation with control and normal pregnant rats on days 13 and 20 of gestation, we observed significant increase of urine volume, 24 h urinary Na excretion, plasma levels of ADM, norepinephrin and PRA and significant decrease of total plasma NO [P<0.0001] and pup weight [P<0.05], while no significant changes were found as regard MAP, 24 h urinary albumin excretion, creatinine clearance and plasma ET-1 level. The current data suggest that the increased ADM concentration seen in L-NAME induced preeclampsia plays a compensatory role and may be necessary to maintain placental vascular resistance and/or fetal circulation, growth and response to a compromised intrauterine environment. ADM administration [which achieved plasma levels of this peptide in the pathophysiological range] to NOS deprived pregnant rats as an animal model of preeclampsia has powerful vasodilator/hypotensive actions and renoprotective effect. Moreover, this study confirms the interaction of ADM with other vasoactive factors that are involved in the pathogenesis of preeclampsia by producing difference in vasoconstrictors/vasodilators balance. Clarification of this possibility must await additional studies and, in particular, the development of specific blackers of ADM secretion or action. Therefore, ADM might be a new target of therapeutic approach to preeclampsia. Manipulations that augment production of this peptide or inhibit its breakdown might find a place in the management of pregnant women with preeclampsia

role of leptin in regulation of thyroid hormones secretion and lipid peroxidation in hypothyroid rats

We addressed the questions of whether leptin is able to modulate thyroid function. Also, we examined the possible mechanistic interaction between leptin and thyroid hormones. To examine our hypothesis that the effects of leptin on energy metabolism may be regulated independently of the TRH/TSH/thyroid hormones, we have studied the effect of systemic administration of leptin on body weight, some metabolic parameters and levels of thyroid hormones and insulin. Since abnormal thyroid functions may be associated with disturbed lipid metabolism, we also examined the effect of leptin administration on lipid per oxidation during hypothyroid state. Hypothyroidism was induced in adult male Wistar rats by giving them 10 mg methimazole daily with their food for 14 days. The hypothyroid status of the rats was verified by blood hormone levels [3, 3', 5'-triiodo-L-thyroxine [T3], thyroxin [T4], and thyroid stimulating hormone [TSH]]. A total number of 40 hypothyroid rats were randomized into four groups [10 rats each], group I: included hypothyroid rats treated with vehicle [V], group II: included hypothyroid rats treated by leptin [L], group III: included hypothyroid rats treated by T3, group IV: included hypothyroid rats treated by both leptin and T3 [L+T3]. An additional group of 10 healthy intact euthyroid rats served as the normal control group [group V]. Initial body weight was measured before the start of leptin and/or T3 treatment and then at the termination of 3 weeks experiment. At the end of the experiments, the serum was used for measurement of cholesterol, triglycerides [TG], free fatty acids [FFA], the levels of leptin, insulin, total T3, T4, TSH, and lipid peroxide. Vehicle treated hypothyroid rats had significant decrease of serum levels of T3, T4, insulin, TG and FFA, and significant increase of TSH and cholesterol levels, while body weight, leptin and lipid peroxide levels were unchanged as compared to controls. Leptin treatment of hypothyroid rats resulted in significant increase of serum leptin levels accompanied by significant increase of FFA and lipid peroxide levels, and significant decrease of body weight, T3, insulin, cholesterol, and TG levels, while, T4 and TSH levels were unchanged as compared to vehicle treated rats. Comparing leptin treated rats with controls, serum T3, T4, TG, insulin levels and body weight were significantly reduced. TSH, leptin, and lipid peroxide levels were significantly increased, while cholesterol and FFA levels were normalized. T3 treatment of hypothyroid rats produced significant decrease of TSH and cholesterol levels and significant increase ofT3, TG, lipid peroxide levels and body weight, and no changes in T4, leptin, FFA, and insulin levels as compared to vehicle treated rats. Comparing T3 treated rats with controls, serum T3, T4, TG, FFA, and insulin levels were significantly reduced, while TSH, cholesterol, lipid peroxide levels and body weight were significantly increased and no change in leptin levels. Combined leptin and T3 treatment caused significant decrease of serum TSH, leptin, cholesterol, TG, FFA, insulin and levels and increase of serum T3, lipid peroxide levels and body weight. No changes in T4 levels were detected as compared to leptin treated rats. By comparing rats treated by both leptin and T3 to controls, there were significant increase of TSH, leptin, lipid peroxide levels and decrease of T4, TG, FFA, insulin levels and body weight and no changes in T3 and cholesterol levels. The current study demonstrates that leptin is capable of reducing body weight, stimulating lipid metabolism and lipid peroxidation in hypothyroid state in rats. It also suggests that the effect of leptin in modulating energy metabolism are not mediated be secondary thyroid messages and are not dependent on a normal thyroid status. The thyroid gland does not constitute an integral component of the leptin action mechanism. However, leptin and thyroid hormones may share some common downstream action sites and can thus act additively, although independently, to enhance calorigenic metabolism, increase lipid peroxidation and attenuate leptin-induced reduction of body weight

Adrenomedullin level in cirrhotic rats: relationship with renal functions and some vasoconstrictors

Purpose: to assess the role of endothelial factors as adrenomedullin [AM] and nitric oxide [NO] in modulating intrahepatic circulation and the role of NO inhibitors. Also, to investigate their relationship with some renal functions and some vasoconstrictors as norepinephrine [NE] and plasma rennin activity [PRA]. a significant increase of AM levels, plasma and urinary No was observed at both groups of cirrhosis. They significantly declined upon No inhibition. The levels were significantly elevated at cirrhosis with ascites than without ascites. PRA significantly increased in both cirrhotic groups with ascites but insignificantly changed at cirrhotic groups without ascites. NE significantly increased at cirrhotic groups [group II and III]. Both NE and PRA significantly declined upon NG nitro L-argenine methylester [L-NAME] administration. AM levels were negatively correlated to mean arterial pressure [MAP] and glomerular filtration rate [GFR]. While it was positively correlated to NE levels, PRA, plasma and urinary NO metabolites, serum Na+ level and urinary sodium excretion [UnaV]. at cirrhosis, there were significantly increased circulating levels of AM, plasma and urinary NO which could be responsible for the arterial vasodilatation. The mechanism of AM effects could be due to NO release. There were increased levels of NE and PRA due to arterial underfilling which activates a baroreceptor mediated neurohumoral response to counterregulate the vasodilatation. NO inhibition revered haemodynamic changes associated with cirrhosis. This raises the possibility of using long term NO inhibition to correct complications associated with cirrhosis and Bilharzial hepatic fibrosis [BHF]