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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+64%) and decreased gelatinolytic activity (-34%) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 +/- 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the alpha 1 IV collagen chain was 2.1 +/- 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1.
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PMID:Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats. 930 Feb 40

We compared the effects of long-term treatment with the angiotensin-converting enzyme inhibitor perindopril and triple therapy (hydrochlorothiazide, reserpine, and hydralazine) on the metabolic and renal features in the SHR/N-corpulent (cp) rat, a genetic model of non-insulin-dependent diabetes mellitus and hypertension. Obese male SHR/N-cp rats (4 to 6 weeks old) were fed a 54% carbohydrate diet containing 18% sucrose and 36% starch. After 2 months on the diet, rats were assigned to one of three groups: one group (n=8) received perindopril (PE); the second group (n=8) received triple therapy (TT); and the third group (n=8) did not receive therapy. Treatment was maintained for 3 to 4 months. Body weight, food intake, and fasting levels of serum glucose and insulin did not differ among the three groups. Control rats exhibited progressive proteinuria in parallel with the rise in systolic blood pressure (SBP). Both PE and TT equally lowered SBP to normal levels and reduced proteinuria in treated rats. However, the reduction of proteinuria was greater and more sustained with PE than with TT (P<.05), whereas the effect of TT on proteinuria was delayed. Plasma renin activity was increased in PE and TT rats compared with control rats (P<.02). Semiquantitative analysis of renal lesions showed that the percentage of glomeruli with mesangial expansion and sclerosis and the tubulointerstitial score (an index of severity of tubulointerstitial lesions, namely tubular atrophy, inflammatory cellular infiltrates, and interstitial fibrosis) was reduced in both PE and TT rats. However, the reduction of glomerulosclerosis and tubulointerstitial lesions was greater in PE than in TT rats (P<.01). The percentage of glomerular sclerosis was positively correlated with the severity score of tubulointerstitial lesions (r=.60, P<.01). We conclude that PE is more effective than TT in halting the progression of proteinuria in the SHR/N-cp rat with non-insulin-dependent diabetes mellitus and hypertension. The antiproteinuric effect of PE is associated with significant reduction in glomerulosclerosis and tubulointerstitial lesions, independent of the effect of treating hypertension.
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PMID:Perindopril ameliorates glomerular and renal tubulointerstitial injury in the SHR/N-corpulent rat. 936 81

Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis of the liver, kidney, and adipose tissue, and exhibited a severe reduction in body fat. Expression of the transgene in hepatocytes resulted in increased collagen deposition, altered lobular organization, increased hepatocyte turnover, and in extreme cases, hemorrhage and thrombosis. Renal expression of the transgene was localized to the proximal tubule epithelium, and was associated with tubulointerstitial fibrosis, characterized by excessive collagen deposition and increased fibronectin and plasminogen activator inhibitor-1 immunoreactivity. Pronounced glomerulosclerosis was evident, and hydronephrosis developed with low penetrance. Expression of TGF-beta1 in white and brown adipose tissue resulted in a lipodystrophy-like syndrome. All white fat depots and brown fat pads were severely reduced in size, and exhibited prominent fibroplasia. This reduction in WAT was due to impaired adipose accretion. Introduction of the transgene into the ob/ob background suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. These studies strengthen the link between TGF-beta1 expression and fibrotic disease, and demonstrate the potency of TGF-beta1 in modulating mesenchymal cell differentiation in vivo.
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PMID:Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. 938 33

To evaluate the effect of insulin and/or triglycerides on the pathogenesis of glomerulosclerosis, acarbose (BAYg5421), an inhibitor of intestinal alpha-glucosidases, was administered as a dietary admix (40 mg/100 g chow) to Zucker obese rats (ZOA), from 1.5 months until sacrifice at 1.5, 5, 8, 10 and 15 months. Obese (ZO) and lean (ZL) rats served as controls. Despite a similar food intake, ZOA weighed less than ZO at all ages. Acarbose reduced serum triglycerides at all ages, and insulin until 10 months. Glycemia remained normal in all groups. Proteinuria developed with age and to a greater degree in ZO than in ZOA rats. In ZL, a faint proteinuria appeared only in the oldest animals. Glomerulosclerosis, tubular and interstitial lesions rapidly affected ZO kidneys. These lesions were reduced in ZOA until 10 months. Acarbose did not modify the hypertrophy of the glomeruli that developed after three months, but slowed down the expansion of the mesangial domain seen in ZO. Thus, by reducing the amount of ingested glucose, acarbose yielded a normal glycemia with a lesser production of insulin and reduced renal impairment. Therefore, insulin could be a key factor involved in the pathogenesis of glomerulosclerosis, either directly or through a control of triglyceride concentrations.
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PMID:Reduction of insulin and triglycerides delays glomerulosclerosis in obese Zucker rats. 940 98

1. Obesity is the most common nutritional disorder in the US and is a major cause of human essential hypertension. Although the precise mechanisms by which obesity raises blood pressure (BP) are not fully understood, there is clear evidence that abnormal kidney function plays a key role in obesity hypertension. 2. Obesity increases tubular reabsorption and this shifts pressure natriuresis towards higher BP. The increased tubular reabsorption is not directly related to hyperinsulinaemia, but is closely linked to activation of the sympathetic and renin-angiotensin systems, and possible changes in intrarenal physical forces caused by medullary compression due to accumulation of adipose tissue around the kidney and increased extracellular matrix within the kidney. 3. Obesity is also associated with marked renal vasodilation and increased glomerular filtration rate, which are compensatory responses that help overcome the increased tubular reabsorption and maintain sodium balance. However, chronic renal vasodilation causes increased hydrostatic pressure and wall stress in the glomeruli which, along with increased lipids and glucose intolerance, may cause glomerulosclerosis and loss of nephron function in obese subjects. Because obesity is a primary cause of essential hypertension as well as type II diabetes, there is good reason to believe that obesity may also be the most frequent cause of end-stage renal disease. 4. Future research is needed to determine the mechanisms by which excess weight gain activates the neurohumoral systems and alters renal structure and function. Because of the high prevalence of obesity in most industrialized countries, unravelling these mechanisms will likely provide a better understanding of the pathophysiology of human essential hypertension and chronic renal failure.
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PMID:Abnormal kidney function as a cause and a consequence of obesity hypertension. 949 61

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1 alpha), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 +/- 3 and 138 +/- 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 +/- 6.7 versus 1.1 +/- 0.1 mg/ml) and albuminuric (8.3 +/- 2.9 versus 0.4 +/- 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 +/- 24 versus 62 +/- 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 +/- 1.6 versus 27.2 +/- 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.
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PMID:Elevated renal endothelin-I clearance and mRNA levels associated with albuminuria and nephropathy in non-insulin-dependent diabetes mellitus: studies in obese fa/fa Zucker rats. 949 94

We observed that some patients do not develop hypoalbuminemia despite the presence of massive proteinuria. To investigate whether the absence or presence of hypoalbuminemia could be a marker in the distinction between idiopathic focal segmental glomerulosclerosis (FSG) and FSG secondary to hyperfiltration, we reviewed all our patients with biopsy-proven FSG and persistent nephrotic-range proteinuria (>3.5 g/24 h). Patients who met these conditions were then separated into those with hypoalbuminemia (serum albumin level <3 g/dL; group I; n = 19) and those with normoalbuminemia (>3.5 g/24 h; group II; n = 18). All group I patients had nephrotic edema in contrast with the absence of edema in all group II patients. Serum cholesterol and triglyceride levels were significantly greater in group I. All group I patients had been diagnosed with idiopathic FSG. The diagnoses of group II patients were FSG secondary to massive obesity in eight patients (44%), vesicoureteral reflux in five patients (27%), and renal mass reduction in three patients (16%); only two patients (11%) in this group had idiopathic FSG. The case histories of 19 other patients with nephrotic-range proteinuria associated with hyperfiltering disorders (reflux nephropathy, massive obesity, renal mass reduction), but without renal biopsy, were also reviewed; despite massive proteinuria (5.8 +/- 3.1 g/24 h), serum albumin and total protein levels were always within normal values. In conclusion, patients with FSG secondary to hyperfiltration do not develop hypoalbuminemia or the other characteristic complications of nephrotic syndrome, despite the presence of massive proteinuria values.
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PMID:Absence of hypoalbuminemia despite massive proteinuria in focal segmental glomerulosclerosis secondary to hyperfiltration. 991 67

Hyperlipidemia accelerates the progression of human renal disease, and its control is becoming an important component of therapy for patients with renal failure. The biologic basis for these observations remains poorly understood. This review summarizes recent data from animal models which show how lipoproteins interact with cells directly to cause renal injury. Data are presented from recent studies on the obese Zucker rat, a metabolic model of hyperlipidemia, obesity, and glomerular sclerosis, showing that triglyceride-containing lipoproteins may mediate glomerular injury. The biochemical basis for therapy is also discussed, including actions of lipid-lowering agents apart from their effect on serum lipids, and the use of polyunsaturated fatty acids as dietary therapy. Animal models are a crucial tool for the further elucidation of mechanisms of lipoprotein-mediated glomerular injury.
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PMID:Hyperlipidemia and renal disease: the use of animal models in understanding pathophysiology and approaches to treatment. 1037 11

Renal hemodynamic features in obese non-insulin-dependent diabetic rats remain unknown. We investigated renal hemodynamic and morphologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at the age of 5 and 10 months compared with age-matched lean nondiabetic control rats (LETO). OLETF rats showed obesity compared with age-matched LETO rats. Hyperglycemia was mild in 5-month-old OLETF rats and moderate in 10-month-old OLETF rats. The absolute value for glomerular filtration rate (GFR) was significantly higher in OLETF rats than in age-matched LETO rats at the age of 5 and 10 months. Ten-month-old OLETF rats had significantly higher absolute values for renal plasma flow (RPF) than age-matched LETO rats but not 5-month-old OLETF rats. Stepwise multiple regression analysis revealed that body weight was a powerful determinant of GFR and RPF. When factored for body weight, no difference in GFR was demonstrated between 5-month-old OLETF and LETO rats, whereas 10-month-old OLETF rats still had significantly higher GFR and RPF than age-matched LETO rats. Renal hypertrophy was demonstrated in both 5- and 10-month-old OLETF rats even when factored for body weight. Glomerular volume was significantly increased in 10-month-old OLETF rats, but the ratio of glomerular volume to body weight was not different among the groups. Both absolute value for glomerular capillary length free from mesangial area and the value factored for glomerular area were significantly longer in OLETF rats than in age-matched LETO rats. Mesangial matrix expansion was remarkable in 10-month-old OLETF rats, and the glomerular sclerosis index was significantly higher in 10-month-old OLETF rats than in age-matched LETO rats. Stepwise multiple regression analysis revealed that body weight, hemoglobin A1c, and hypertriglyceridemia were powerful determinants for kidney weight and glomerular volume. These data suggest that renal hyperfiltration and hypertrophy observed in 10-month-old OLETF rats are related to diabetic metabolic disorders and that obesity-related conditions may be involved in the renal hemodynamic and morphologic features in OLETF rats.
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PMID:Renal hemodynamics in Otsuka Long-Evans Tokushima fatty rat, a model rat of spontaneous non-insulin-dependent diabetes mellitus with obesity. 1056 Sep 42

Abnormal kidney function is an important cause as well as a consequence of obesity. Excess renal sodium reabsorption, probably in the loop of Henle, and a hypertensive shift of pressure natriuresis play a major role in initiating increased blood pressure associated with weight gain. The mechanisms responsible for increased sodium reabsorption and altered pressure natriuresis in obesity include activation of the renin-angiotension and sympathetic nervous systems, and physical compression of the kidneys due to accumulation of intrarenal fat and extracellular matrix. Sympathetic activation may be mediated, in part, by elevated circulating leptin and interactions with neuropeptides in the hypothalamus. Renal remodeling and extracellular matrix proliferation likely involve complex interactions between intrarenal physical forces, neurohumoral factors, and local growth factors and cytokines. Although glomerular hyperfiltration and increased arterial pressure help to compensate for increased renal tubular reabsorption in the early phases of obesity, these changes also increase glomerular capillary wall stress which, along with activation of neurohumoral systems and increased lipids and glucose intolerance, cause glomerular cell proliferation, matrix accumulation, and eventually glomerulosclerosis and loss of nephron function in the early phases of obesity. This creates a slowly developing vicious cycle that requires additional increases in arterial pressure to maintain sodium balance and therefore makes effective antihypertensive therapy more difficult. Because obesity is the main cause of Type 2 diabetes and an important cause of human essential hypertension, it seems likely that obesity is also one of the most important risk factors for end-stage renal disease.
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PMID:Mechanisms of hypertension and kidney disease in obesity. 1084 55


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