Elevated Renal Endothelin-1 Clearance and mRNA Levels Associated with Albuminuria and Nephropathy in Non-Insulin-Dependent Diabetes Mellitus: Studies in Obese fa/fa Zucker Rats

1997 ◽  
Vol 93 (6) ◽  
pp. 565-571 ◽  
Author(s):  
N. C. Turner ◽  
P. J. Morgan ◽  
A. C. Haynes ◽  
M. Vidgeon-Hart ◽  
N. Toseland ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Urinary Excretion ◽  
Cyclic Gmp ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Zucker Rats ◽  
Dependent Diabetes Mellitus ◽  
Mrna Levels ◽  
Zucker Rat ◽  
Insulin Dependent

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 F1α), 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.

scholarly journals Alterations in glomerular proteoglycan metabolism in experimental non-insulin dependent diabetes mellitus.

1993 ◽  
Vol 3 (10) ◽  
pp. 1694-1704
Author(s):  
P Fioretto ◽  
W F Keane ◽  
B L Kasiske ◽  
M P O'Donnell ◽  
D J Klein
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Zucker Rats ◽  
Dependent Diabetes Mellitus ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Insulin Dependent ◽  
Obese Zucker Rats

Glomerular proteoglycans (PG) are important in modulating extracellular matrix assembly and glomerular permselectivity. In the obese Zucker rat, an experimental model of non-insulin dependent diabetes mellitus, expansion of the mesangial matrix, and microalbuminuria occur before the development of overt renal disease. The in vivo incorporation of (35S)sulfate into glomerular PG in 12-wk-old obese Zucker rats at the onset of microalbuminuria was compared with that of 12-wk-old lean Zucker rats. Specific (35S)sulfate incorporation into glomerular PG over 8 h was increased by 57% in obese rats compared with lean rats, suggesting increased PG synthesis. However, at variance with the observation in experimental models of insulin-dependent diabetes mellitus, the proportion of total glomerular (35S)PG released by heparin treatment was unchanged. Heparan sulfate (HS)-PG constituted over 60% of radiolabeled de novo synthesized glomerular PG. Similar proportions of HS-PG were extracted from the glomeruli of obese and lean rats. Isolated glomeruli spontaneously released two HS-PG, which constituted approximately 30% of total glomerular (35S)PG. On the basis of their chromatographic and electrophoretic patterns, these PG were similar in obese and lean rats. Heparin treatment of isolated glomeruli released an additional HS-PG, which appeared to be derived primarily from the glomerular extracellular matrix compartment and not from the detergent soluble cell fraction. Heparin-releasable HS-PG from both the lean and obese Zucker rats eluted at a KAV of 0.31 from Sepharose CL-6B chromatographic columns, indicating a hydrodynamic size similar to that reported for glomerular basement membrane HS-PG. However, gel electrophoresis demonstrated faster migration of the HS-PG released by heparin from the glomeruli of obese Zucker rats, suggesting increased electronegativity. Thus, early in the course of nephropathy in the obese Zucker rat, there is increased glomerular PG synthesis with no change in the proportions of the constitutively releasable and heparin-releasable HS-PG. Whether electrophoretic abnormalities of the heparin-releasable HS-PG observed in the obese rats contribute to the development of albuminuria and/or mesangial matrix expansion remains to be established.

Distinct Associations of HbA1c and the Urinary Excretion of Pentosidine, an Advanced Glycosylation End-product, with Markers of Endothelial Function in Insulin-dependent Diabetes mellitus

1998 ◽  
Vol 80 (07) ◽  
pp. 52-57 ◽  
Author(s):  
Ronald Smulders ◽  
Casper Schalkwijk ◽  
Ab Donker ◽  
Victor van Hinsbergh ◽  
Johan TeKoppele ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Function ◽  
Urinary Excretion ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Dependent Diabetes Mellitus ◽  
Control Group ◽  
Advanced Glycosylation End Products ◽  
Insulin Dependent ◽  
Advanced Glycosylation

SummaryDysfunction of the vascular endothelium is considered an early step in the development of diabetic angiopathy. Hyperglycaemia results in endothelial dysfunction, both through direct effects of glucose and through formation of advanced glycosylation end-products (AGEs). We hypothesized that the effects of glucose and AGEs on endothelial function in insulin-dependent diabetes mellitus (IDDM) are distinct and are reflected by distinct plasma markers of endothelial function. We therefore measured plasma levels of von Willebrand factor (vWF), soluble (s) E-selectin and vascular cell adhesion molecule-1 (sVCAM-1), and evaluated the relationship with HbA1c and urinary excretion of pentosidine, an AGE product, in 56 patients with IDDM. Urinary pentosidine excretion was higher in the diabetic than in a control group (n = 60) of similar age (P <0.0001) and showed a steeper increase with age (P <0.02 vs controls). In the diabetic group, sE-selectin was correlated to HbA1c (r = 0.52, P <0.0001), whereas sVCAM-1 was not (r = 0.11, P = 0.47). In contrast, sVCAM-1 showed a trend towards a correlation with log (pentosidine excretion) (r = 0.27, P = 0.06), whereas sE-selectin did not (r = –0.16, P = 0.27). Log(vWF) was correlated to HbA1c (r = 0.50, P <0.0001) and tended to correlate with log (pentosidine excretion) (r = 0.25, P = 0.07). Multivariate analyses with both pentosidine and HbA1c as independent variables showed significant associations of sE-selectin with HbA1c, of sVCAM-1 with pentosidine, and of log(vWF) with both HbA1c and pentosidine (all P-values <0.02). Our results imply that the effects of glucose and AGEs on the endothelium can be reflected by distinct endothelial markers. Plasma sE-selectin may reflect short-term effects of glucose on the endothelium, sVCAM-1 the effects of AGEs, and vWF the combined effect of glucose and AGEs.

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