Reduced renal dopamine D₁receptor function in streptozotocin-induced diabetic rats

Abstract

Dopamine, via activation of renal D(1) receptors, inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with type I diabetes. However, it is not known whether the response to D(1) receptor activation is altered in type I diabetes. The present study was designed to examine the effect of streptozotocin-induced type I diabetes on renal D(1) receptor expression and function. Streptozotocin treatment of Sprague-Dawley rats caused a fourfold increase in plasma levels of glucose along with a significant decrease in insulin levels compared with control rats. Intravenous administration of SKF-38393, a D(1) receptor agonist, caused a threefold increase in sodium excretion in control rats. However, SKF-38393 failed to produce natriuresis in diabetic rats. SKF-38393 caused a concentration-dependent inhibition of Na-K-ATPase activity in renal proximal tubules of control rats. However, the ability of SKF-38393 to inhibit Na-K-ATPase activity was markedly diminished in diabetic rats. D(1) receptor numbers and protein abundance as determined by [(3)H]SCH-23390 ligand binding and Western blot analysis were markedly reduced in diabetic rats compared with control rats. Moreover, SKF-38393 failed to stimulate GTP gamma S binding in proximal tubular membranes from diabetic rats compared with control rats. We conclude that the natriuretic response to D(1) receptor activation is reduced in type I diabetes as a result of a decrease in D(1) receptor expression and defective receptor G protein coupling. These abnormalities may contribute to the sodium retention associated with type I diabetes.

Angiotensin II Type 2 Receptor Agonist Directly Inhibits Proximal Tubule Sodium Pump Activity in Obese But Not in Lean Zucker Rats

“…18 Similarly, an upregulation of the renal AT 2 receptor function on tubular sodium metabolism was found in streptozotocin-induced diabetic rats, 35 where dopamine D 1 receptors also are shown to be defective. 36 In addition to the defective dopamine D 1 receptor, we 3,11 and others 23 have reported enhanced Ang II function on tubular sodium transport and hyperantinatriuretic activity in obese compared with lean Zucker rats. Compared with the AT 2 receptors, in general, the AT 1 receptors are the predominant receptor subtype; therefore, the net effect of Ang II is believed to be mediated via the activation of the AT 1 receptors.…”

Mechanisms of Oxidative Stress-Induced Increase in Salt Sensitivity and Development of Hypertension in Sprague-Dawley Rats

“…Blood pressure and heart rate were continuously recorded on a Grass polygraph (model 7D, Grass Instrument). 21 For aortic preparations, a midline abdominal incision was made, and thoracic aortas were removed and immediately placed in Krebs-Henseleit buffer (mM: NaCl 118.4, KCl 4.7, CaCl 2 2.5, KH 2 PO 4 1.2, MgSO 4 1.2, NaHCO 3 25.0, and glucose 10.0 [pH 7.4]). The aortas were cleaned of adherent tissue and cut into rings with minimum damage to endothelium.…”

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D 1A Receptor in Obese Zucker Rats

“…16 Briefly, plasma membrane samples (50 g) were incubated with 100 nmol/L [ 3 H] SCH-23390 (specific activity, 86 Ci/mmol; Dupont NEN) at 25°C for 1.5 hours. Nonspecific binding was defined by using 10 mol/L SCH-23390.…”

“…16 The D 1A receptor bands were densitometrically quantified by using Scion Image software provided by National Institutes of Health.…”