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.
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.
Turner
N C
NC
Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire, U.K.
Morgan
P J
PJ
Haynes
A C
AC
Vidgeon-Hart
M
M
Toseland
N
N
Clapham
J C
JC
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D006152:Cyclic GMP / Q000652:urine; D003920:Diabetes Mellitus / Q000503:physiopathology* / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology* / Q000652:urine; D019332:Endothelin-1 / Q000235:genetics / Q000652:urine*; D007150:Immunohistochemistry; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D009765:Obesity / Q000503:physiopathology* / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011924:Rats, Zucker; D018709:Statistics, Nonparametric; D013929:Thromboxane B2 / Q000652:urine
D019332:Endothelin-1; D012333:RNA, Messenger; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D006152:Cyclic GMP