Cardiovascular dysfunction in Zucker obese and Zucker diabetic fatty rats: role of hydronephrosis

Recent studies in our laboratory using the Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rat models resulted in unexpectedly high mortality rates in all genotypes including healthy homozygous lean Zucker rats, possibly because of renal dysfunction. Therefore, we evaluated left ventricular (LV) and kidney morphology and function in young ZO, Zucker diabetic fatty obese (ZDFO), homozygous Zucker/ZDF lean (ZL), and Sprague-Dawley (SD) rats. Hydronephrosis was evident in ZL, ZO, and ZDFO but not SD kidneys. ZDFO rats exhibited impaired LV shortening and relaxation with increased arterial stiffness. LV wall thickness was lower and LV end-systolic wall stress was higher in ZDFO compared with SD rats. Plasma ANG II was lower in ZO and ZDFO rats, which may be a result of reduced renal parenchyma with hydronephrosis; norepinephrine was higher in ZDFO rats than SD controls. Covariate analysis indicated that LV end-systolic wall stress was associated with renal dysfunction. The presence of hydronephrosis and its association with LV dysfunction potentially limits the ZDF model for study of the effects of diabetes on renal and cardiovascular function.     

Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin

Increasing renal pelvic pressure results in PGE(2)-mediated release of substance P. Substance P increases afferent renal nerve activity (ARNA), which leads to a reflex increase in urinary sodium excretion (U(Na)V). Endogenous ANG II modulates the responsiveness of renal mechanosensory nerves. The ARNA and U(Na)V responses are suppressed by low- and enhanced by high-sodium diet. We examined whether the ARNA responses are altered in rats with congestive heart failure (CHF), a condition characterized by increased ANG II and sodium retention. The ARNA responses to increasing renal pelvic pressure 相似文献   

Differential adipose tissue inflammatory state in obese nondiabetic Zucker fatty rats compared to obese diabetic zucker diabetic fatty rats

Adipose tissue (AT) inflammation is linked to the pathogenesis of diabetes in obesity. Here, we compare the AT inflammatory state of 2 animal models of obesity and obesity plus diabetes, respectively. Obese nondiabetic ZF rats exhibited a trend towards increased proportions of CD11b positive cells in the adipose tissue stroma vascular fraction suggesting a state of increased AT inflammation compared to their lean littermates, but no alterations in systemic inflammatory parameters. In contrast, obese diabetic ZDF rats exhibited systemic as well as local AT inflammation with elevated levels of circulating Regulated upon Activation, Normal T-cell Expressed and Secreted Protein (Rantes), interleukin 1β (IL-1β) and monocyte chemotactic protein 1 (MCP-1), and an increased infiltration of adipose tissue CD11b positive cells. Our data provide a novel phenotypic characterisation of 2 common metabolic animal models and suggest an association of obesity with local inflammation in adipose tissue, and an association of diabetes with local inflammation in adipose tissue plus systemic inflammation. AT inflammation in obesity might therefore initiate a process that above a certain limits finally results in systemic inflammation and diabetes.     

Progression of coronary and mesenteric vascular dysfunction in Zucker obese and Zucker diabetic fatty rats

We investigated the progression of vascular dysfunction associated with the metabolic syndrome with and without hyperglycemia in lean, Zucker obese, and Zucker diabetic fatty (ZDF) rats. Responses of aorta and small coronary and mesenteric arteries were measured to endothelium-dependent and -independent vasodilators. Indices of oxidative stress were increased in serum from ZDF rats throughout the study, whereas values were increased in Zucker obese rats later in the study [thiobarbituric acid reactive substances: 0.45 +/- 0.02, 0.59 +/- 0.03 (P < 0.05), and 0.58 +/- 0.03 (P < 0.05) mug/ml in serum from 28- to 40-wk-old lean, Zucker obese, and ZDF rats, respectively]. Acetylcholine (ACh)-induced relaxation was not altered in vessels from lean animals from 8-40 wk. ACh-induced relaxation was nearly abolished in coronary arteries from 28- to 36-wk-old Zucker obese rats and by 16-36 wk in ZDF rats and was attenuated in aorta and mesenteric vessels from ZDF rats [%relaxation to 10 muM ACh: 72.2 +/- 7.1, 17.9 +/- 5.9 (P < 0.05), and 23.0 +/- 4.5 (P < 0.05) in coronary vessels; and 67.9 +/- 9.2, 50.1 +/- 5.5, and 42.3 +/- 4.7 (P < 0.05) in mesenteric vessels from 28- to 40-wk-old lean, Zucker obese, and ZDF rats, respectively]. The attenuated ACh-induced relaxation was improved when vessels were incubated with tiron, suggesting superoxide as a mechanism of endothelial dysfunction. Sodium nitroprusside-induced relaxation was not altered in aorta or coronary arteries and was potentiated in mesenteric arteries from Zucker obese rats. Our data suggest that diabetes enhances the progression of vascular dysfunction. Increases in indices of oxidative stress precede the development of dysfunction and may serve as a marker of endothelial damage.     

Progression of vascular and neural dysfunction in sciatic nerves of Zucker diabetic fatty and Zucker rats

We have examined the progression of vascular and neural deficits in Zucker rats, Zucker diabetic fatty (ZDF) diabetic rats, and age-matched lean ZDF rats from 8 to 40 wk of age. Both the ZDF diabetic and Zucker rats were glucose intolerant at 8 wk of age. The Zucker rats did not become hyperglycemic but were hyperinsulinemic through 32 wk of age. All ZDF diabetic rats became hyperglycemic by 8 wk of age. Through their life span, serum free fatty acids and triglycerides levels were significantly higher in Zucker and ZDF diabetic rats compared with age-matched lean ZDF rats. After 24 and 28 wk of age, endoneurial blood flow was significantly decreased in ZDF diabetic and Zucker rats. Motor nerve conduction velocity was significantly decreased after 12-14 wk of age in ZDF diabetic rats and at 32 wk of age in Zucker rats. ACh-mediated vascular relaxation of epineurial arterioles of the sciatic nerve was impaired after 8-10 wk of age in ZDF diabetic rats and after approximately 16 wk of age in Zucker rats. In contrast, vascular relaxation mediated by calcitonin gene-related peptide was impaired significantly after 28 wk of age in ZDF diabetic rats but not impaired in Zucker rats up to 40 wk of age. Markers of oxidative stress were differentially elevated in ZDF diabetic rats and Zucker rats. These data indicate that vascular and neural dysfunction develops in both Zucker and ZDF diabetic rats but at different rates, which may be the result of hyperglycemia.     

Impaired NO-dependent dilation of skeletal muscle arterioles in hypertensive diabetic obese Zucker rats

This study determined alterations to nitric oxide (NO)-dependent dilation of skeletal muscle arterioles from obese (OZR) versus lean Zucker rats (LZR). In situ cremaster muscle arterioles from both groups were viewed via television microscopy, and vessel dilation was measured with a video micrometer. Arteriolar dilation to acetylcholine and sodium nitroprusside was reduced in OZR versus LZR, although dilation to aprikalim was unaltered. NO-dependent flow-induced arteriolar dilation (via parallel microvessel occlusion) was attenuated in OZR, impairing arteriolar ability to regulate wall shear rate. Vascular superoxide levels, as assessed by dihydroethidine fluorescence, were elevated in OZR versus LZR. Treatment of cremaster muscles of OZR with the superoxide scavengers polyethylene glycol-superoxide dismutase and catalase improved arteriolar dilation to acetylcholine and sodium nitroprusside and restored flow-induced dilation and microvascular ability to regulate wall shear rate. These results suggest that NO-dependent dilation of skeletal muscle microvessels in OZR is impaired due to increased levels of superoxide. Taken together, these data suggest that the development of diabetes and hypertension in OZR may be associated with an impaired skeletal muscle perfusion via an elevated vascular oxidant stress.     

Impaired skeletal muscle perfusion in obese Zucker rats

Skeletal muscle arterioles from obese Zucker rats (OZR) exhibit oxidant stress-based alterations in reactivity, enhanced alpha-adrenergic constriction, and reduced distensibility vs. microvessels of lean Zucker rats (LZR). The present study determined the impact of these alterations for perfusion and performance of in situ skeletal muscle during periods of elevated metabolic demand. During bouts of isometric tetanic contractions, fatigue of in situ gastrocnemius muscle of OZR was increased vs. LZR; this was associated with impaired active hyperemia. In OZR, vasoactive responses of skeletal muscle arterioles from the contralateral gracilis muscle were impaired, due in part to elevated oxidant tone; reactivity was improved after treatment with polyethylene glycol-superoxide dismutase (PEGSOD). Arterioles of OZR also exhibited increased alpha-adrenergic sensitivity, which was abolished by treatment with phentolamine (10-5 M). Intravenous infusion of phentolamine (10 mg/kg) or PEG-SOD (2,000 U/kg) in OZR altered neither fatigue rates nor active hyperemia from untreated levels; however, combined infusion improved performance and hyperemia, although not to levels in LZR. Microvessel density in the contralateral gastrocnemius muscle, determined via histological analyses, was reduced by approximately 25% in OZR vs. LZR, while individual arterioles from the contralateral gracilis muscle demonstrated reduced distensibility. These data suggest that altered arteriolar reactivity contributes to reduced muscle performance and active hyperemia in OZR. Further, despite pharmacological improvements in arteriolar reactivity, reduced skeletal muscle microvessel density and arteriolar distensibility also contribute substantially to reduced active hyperemia and potentially to impaired muscle performance.     

Impaired arachidonic acid-mediated dilation of small mesenteric arteries in Zucker diabetic fatty rats

Arachidonic acid (AA) is a precursor of important vasoactive metabolites, but the role of AA-mediated vasodilation in Type 2 diabetes is not known. Using Zucker diabetic fatty (ZDF) rats, we examined the effects of AA in small mesenteric arteries preconstricted with endothelin. In ZDF rat mesenteric arteries, 1 microM AA produced only one-third the amount of dilation as in vessels from lean control animals. In lean control rats, the effect of AA was significantly and predominantly inhibited by the lipoxygenase inhibitors baicalein and cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC). However, baicalein and CDC had no effect on AA-mediated dilation in ZDF rat mesenteric arteries. The major [3H]AA metabolite produced by isolated mesenteric arteries in both lean and ZDF rats was 12-hydroxyeicosatetraenoic acid (12-HETE), but the amount of [3H]12-HETE produced by ZDF rat vessels was only 36% of that of control vessels. In addition, 12-HETE produced similar amounts of dilation in lean and ZDF rat mesenteric arteries. Immunoblot analysis showed an 81% reduction in 12-lipoxygenase protein in ZDF rat mesenteric arteries. Immunofluorescence labeling showed strong nitrotyrosine signals in ZDF rat mesenteric arteries that colocalized with 12-lipoxygenase in endothelium, and 12-lipoxygenase coprecipitation with anti-nitrotyrosine antibodies was enhanced in ZDF rat vessels. We conclude that AA-mediated relaxation in ZDF rat small mesenteric arteries is impaired due to reduced 12-lipoxygenase protein and activity. Increased oxidative stress and nitration of 12-lipoxygenase may underlie the impairment of AA-mediated relaxation in small mesenteric arteries of diabetic rats.     

Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats

This study determined alterations to hypoxic dilation of isolated skeletal muscle resistance arteries (gracilis arteries; viewed via television microscopy) from obese Zucker rats (OZR) compared with lean Zucker rats (LZR). Hypoxic dilation was reduced in OZR compared with LZR. Endothelium removal and cyclooxygenase inhibition (indomethacin) severely reduced this response in both groups, although nitric oxide synthase inhibition (N(omega)-nitro-L-arginine methyl ester) reduced dilation in LZR only. Treatment of vessels with a PGH(2)-thromboxane A(2) receptor antagonist had no effect on hypoxic dilation in either group. Arterial dilation to arachidonic acid, iloprost, acetylcholine, and sodium nitroprusside was reduced in OZR versus LZR, although dilation to forskolin and aprikalim was unaltered. Treatment of arteries from OZR with oxidative radical scavengers increased dilation to hypoxia and agonists, with no effect on responses in LZR. The restored hypoxic dilation in OZR was abolished by indomethacin. These results suggest that hypoxic dilation of skeletal muscle microvessels from LZR represents the summated effects of prostanoid and nitric oxide release, whereas the impaired response of vessels in OZR may reflect scavenging of PGI(2) by superoxide anion.     

Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats

This study examined skeletal muscle microvessel reactivity to constrictor stimuli in obese (OZR) versus lean Zucker rats (LZR). Gracilis arteries from both rat groups were isolated, cannulated with glass micropipettes, and viewed via television microscopy. Changes in vessel diameter were measured with a video micrometer. Arterial constriction to norepinephrine was elevated in OZR versus LZR, although vasoconstrictor reactivity to endothelin and angiotensin II was unaltered. Differences in reactivity between vessels of LZR and OZR were not explained by the loss of either endothelial nitric oxide synthase or beta-adrenergic receptor function. Reactivity of in situ cremasteric arterioles of OZR to norepinephrine was elevated versus LZR. Treatment with prazosin increased the diameter of in vivo gracilis arteries of OZR to levels determined in LZR and also normalized blood pressure in OZR. These results suggest that the constrictor reactivity of skeletal muscle microvessels in OZR is heightened in response to alpha-adrenergic stimuli and that development of diabetes in OZR may be associated with impaired skeletal muscle perfusion and hypertension due to microvessel hyperreactivity in response to sympathetic stimulation.     

Defect in glucokinase translocation in Zucker diabetic fatty rats

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; micromol.kg(-1).min(-1)) were slightly higher in ZDF (8.4 +/- 0.3 and 53 +/- 7, respectively) than in lean rats (6.2 +/- 0.2 and 45 +/- 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 +/- 350) than in lean rats (150 +/- 14). The ratio of hepatic uridine 5'-diphosphate-glucose 3H specific activity to plasma glucose 3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (micromol.kg(-1).min(-1)), and hepatic glucose cycling (micromol.kg(-1).min(-1)) were higher in ZDF (35 +/- 5, 87 +/- 16, and 33 +/- 10, respectively) compared with lean rats (18 +/- 3, 56 +/- 6, and 11 +/- 2, respectively). [3H]glucose incorporation into glycogen (micromol glucose/g liver) was similar in lean (1.0 +/- 0.7) and ZDF (1.6 +/- 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR (micromol.kg(-1).min(-1)), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (micromol glucose/g liver) were markedly higher in lean (191 +/- 22, 62 +/- 3, and 5.0 +/- 1.4, respectively) but similar in ZDF rats (100 +/- 6, 37 +/- 3, and 1.4 +/- 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation.     

Dysregulated pyruvate dehydrogenase complex in Zucker diabetic fatty rats

The mitochondrial pyruvate dehydrogenase complex (PDC) is inactivated in many tissues during starvation and diabetes. We investigated carbohydrate oxidation (CHO) and the regulation of the PDC in lean and obese Zucker diabetic fatty (ZDF) rats during fed and starved conditions as well as during an oral glucose load without and with pharmacologically reduced levels of free fatty acids (FFA) to estimate the relative contribution of FFA on glucose tolerance, CHO, and PDC activity. The increase in total PDC activity (20-45%) was paralleled by increased protein levels ( approximately 2-fold) of PDC subunits in liver and muscle of obese ZDF rats. Pyruvate dehydrogenase kinase-4 (PDK4) protein levels were higher in obese rats, and consequently PDC activity was reduced. Although PDK4 protein levels were rapidly downregulated (57-62%) in both lean and obese animals within 2 h after glucose challenge, CHO over 3 h as well as the peak of PDC activity (1 h after glucose load) in liver and muscle were significantly lower in obese rats compared with lean rats. Similar differences were obtained with pharmacologically suppressed FFA by nicotinic acid, but with significantly improved glucose tolerance in obese rats, as well as increased CHO and delta increases in PDC activity (0-60 min) both in muscle and liver. These results demonstrated the suppressive role of FFA acids on the measured parameters. Furthermore, the results clearly demonstrate a rapid reactivation of PDC in liver and muscle of lean and obese rats after a glucose load and show that PDC activity is significantly lower in obese ZDF rats.     

Intrarenal oxidative stress and augmented angiotensinogen are precedent to renal injury in Zucker diabetic fatty rats

The Zucker diabetic fatty (ZDF) rat is a model of type II diabetes and metabolic syndrome based on impaired glucose tolerance caused by the inherited insulin-resistance gene. The ZDF rat exhibits progressive nephropathy; however, the detailed mechanisms have remained unclear. This study was performed to examine the possible involvement of enhanced intrarenal angiotensinogen in the development of renal injury in ZDF rats. Genetic pairs of male ZDF rats and control lean rats (N=6 each) were maintained from 12 to 17 weeks of age. At 17 weeks of age, fasting blood glucose and urinary 8-isoprostane levels were significantly higher in ZDF rats compared with the controls. Systolic blood pressure progressively increased in ZDF rats from 120+/-1 to 137+/-1 mmHg during this period. In contrast, systolic blood pressure did not increase in the controls. Kidney angiotensinogen protein levels were significantly increased in ZDF rats compared with the controls (1.83+/-0.34 vs. 1.00+/-0.17, relative ratio). Expression of angiotensin II type 1a receptor mRNA was similar between these groups. The measured indices of renal damage in the present study (glomerular sclerosis, interstitial expansion, glomerular macrophage infiltration, and renal arterial proliferation) were not significantly increased at this stage in ZDF rats. However, we previously showed that the increased reactive oxygen species-related angiotensinogen enhancement plays an important role in the development of renal injury in a genetic salt-sensitive hypertension. Thus, the present data suggest that elevated reactive oxygen species and reactive oxygen species-associated augmentation of intrarenal angiotensinogen may initiate the development of renal injury in ZDF rats.     

Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats

Giant vesicles were used to study the rates of uptake of long-chain fatty acids by heart, skeletal muscle, and adipose tissue of obese and lean Zucker rats. With obesity there was an increase in vesicular fatty acid uptake of 1.8-fold in heart, muscle and adipose tissue. In some tissues only fatty acid translocase (FAT) mRNA (heart, +37%; adipose, +80%) and fatty acid-binding protein (FABPpm) mRNA (heart, +148%; adipose, +196%) were increased. At the protein level FABPpm expression was not changed in any tissues except muscle (+14%), and FAT/CD36 protein content was altered slightly in adipose tissue (+26%). In marked contrast, the plasma membrane FAT/CD36 protein was increased in heart (+60%), muscle (+80%), and adipose tissue (+50%). The plasma membrane FABPpm was altered only in heart (+50%) and adipose tissues (+70%). Thus, in obesity, alterations in fatty acid transport in metabolically important tissues are not associated with changes in fatty acid transporter mRNAs or altered fatty acid transport protein expression but with their increased abundance at the plasma membrane. We speculate that in obesity fatty acid transporters are relocated from an intracellular pool to the plasma membrane in heart, muscle, and adipose tissues.     

Impaired blood pressure recovery to hemorrhage in obese Zucker rats with orthopedic trauma

We have shown that obese Zucker rats with orthopedic trauma (OZT) exhibit a loss of arteriolar tone in skeletal muscle. We hypothesize that the loss of arteriolar tone in OZT blunts vasoconstrictor responses to hemorrhage, resulting in an impaired blood pressure recovery. Orthopedic trauma was induced with soft tissue injury and local injection of bone components in both hindlimbs in lean (LZT) and OZT (11-13 wk). One day after the orthopedic trauma, blood pressure responses following hemorrhage were measured in conscious control lean, control obese, LZT, and OZT. In another set of experiments, the spinotrapezius muscle of control and trauma animals was prepared for microcirculatory observation. Arteriolar responses to phenylephrine (PE) or hemorrhage were determined. Hemorrhage resulted in similar blood pressure responses in control animals and LZT, but the blood pressure recovery following hemorrhage was blunted in the OZT. In the spinotrapezius, OZT exhibited decreased arteriolar tone and blunted vasoconstrictor responses to PE and hemorrhage. Treatment with glibenclamide improved the blood pressure recovery in the conscious OZT and improved the arteriolar tone, and PE induced vasoconstriction in the spinotrapezius of the OZT. Thus, ATP-dependent K(+) channel-mediated loss of arteriolar tone in OZT blunts the arteriolar constriction to hemorrhage, resulting in impaired blood pressure recovery.     

Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats

We measured infarct size after coronary occlusion (30 min) and reperfusion (24 h) in genetic non-insulin-dependent Zucker diabetic fatty (ZDF) rats with and without 4-wk cholesterol feeding. Infarct size was similar in ZDF rats and lean control rats but was significantly larger in cholesterol-fed diabetic rats than in cholesterol-fed lean rats (P < 0.05). Plasma levels of glucose, insulin, and triglycerides were significantly higher in diabetic rats and were not influenced by cholesterol feeding. The increase in total plasma cholesterol induced by cholesterol feeding was significantly greater in diabetic rats than in lean rats (P < 0.05). A significant positive correlation was found between total plasma cholesterol and infarct size (P < 0.05). Myeloperoxidase activity, as an index of neutrophil accumulation, was significantly higher and expression of P-selectin was more marked in the ischemic myocardium of cholesterol-fed diabetic rats than of cholesterol-fed lean rats. Acetylcholine-induced endothelium-dependent relaxation (EDR) of aortic rings was markedly impaired in cholesterol-fed diabetic rats. Thus cholesterol feeding significantly exacerbated myocardial injury produced by coronary occlusion-reperfusion in non-insulin-dependent diabetic rats, possibly because of enhanced expression of P-selectin and impairment of EDR in the coronary bed.     

Angiotensin-(1-7) attenuates diabetic nephropathy in Zucker diabetic fatty rats

Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng·kg(-1)·min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy.     

The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats

The metabolic syndrome is a risk factor that increases the risk for development of renal and vascular complications. This study addresses the effects of chronic administration of the endogenous dipeptide carnosine (β‐alanyl‐L‐histidine, L‐CAR) and of its enantiomer (β‐alanyl‐D‐histidine, D‐CAR) on hyperlipidaemia, hypertension, advanced glycation end products, advanced lipoxidation end products formation and development of nephropathy in the non‐diabetic, Zucker obese rat. The Zucker rats received a daily dose of L‐CAR or D‐CAR (30 mg/kg in drinking water) for 24 weeks. Systolic blood pressure was recorded monthly. At the end of the treatment, plasma levels of triglycerides, total cholesterol, glucose, insulin, creatinine and urinary levels of total protein, albumin and creatinine were measured. Several indices of oxidative/carbonyl stress were also measured in plasma, urine and renal tissue. We found that both L‐ and D‐CAR greatly reduced obese‐related diseases in obese Zucker rat, by significantly restraining the development of dyslipidaemia, hypertension and renal injury, as demonstrated by both urinary parameters and electron microscopy examinations of renal tissue. Because the protective effect elicited by L‐ and D‐CAR was almost superimposable, we conclude that the pharmacological action of L‐CAR is not due to a pro‐histaminic effect (D‐CAR is not a precursor of histidine, since it is stable to peptidic hydrolysis), and prompted us to propose that some of the biological effects can be mediated by a direct carbonyl quenching mechanism.     

Pioglitazone reverses down-regulation of cardiac PPARgamma expression in Zucker diabetic fatty rats

Peroxisome proliferator-activated receptor-gamma (PPARgamma) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPARgamma in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPARgamma agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPARgamma, glucose transporter-4 and alpha-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPARgamma, glut-4, and alpha-MHC expression levels in diabetic ZDF rats. Cardiac [(18)F]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPARgamma agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPARgamma expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin.