Exposure to Maternal Diabetes Mellitus Causes Renal Dopamine D ₁ Receptor Dysfunction and Hypertension in Adult Rat Offspring

Abstract

Epidemiological and experimental studies suggest that maternal diabetes programs hypertension that is associated with impaired sodium excretion in the adult offspring. However, the underlying mechanisms are not clear. Because dopamine receptor function is involved in the pathogenesis of hypertension, we hypothesized that impaired renal dopamine D1 receptor function is also involved in the hypertension in offspring of maternal diabetes. Maternal diabetes was induced by a single intraperitoneal injection of streptozotocin (35 mg/kg) to pregnant Sprague-Dawley rats at day 0 of gestation. Compared with the offspring of mothers injected with citrate buffer (control mother offspring, CMO), the diabetic mother offspring (DMO) had increased systolic blood pressure and impaired D1 receptor-mediated diuresis and natriuresis, accompanied by increased renal protein kinase C (PKC) expression and activity, G protein-coupled receptor kinase-2 (GRK-2) expression, D1 receptor phosphorylation, D1 receptor/Gαs uncoupling, and loss of D1 receptor-mediated inhibition of Na+-K+-ATPase activity in renal proximal tubule (RPT) cells from DMO. Inhibition of PKC reduced the increased GRK-2 expression and normalized D1 receptor function in primary cultures of RPT cells from DMO. In addition, DMO, relative to CMO, in vivo, had increased oxidative stress, indicated by decreased renal glutathione and increased renal malondialdehyde and urine 8-isoprostane. Normalization of oxidative stress with tempol also normalized the renal D1 receptor phosphorylation, D1 receptor-mediated diuresis and natriuresis, and blood pressure in DMO. Our present study indicates that maternal diabetes-programed-hypertension in the offspring is caused by impaired renal D1 receptor function due to oxidative stress that is mediated by increased PKC-GRK-2 activity.

Novel Detection and Restorative Levodopa Treatment for Preclinical Diabetic Retinopathy

“…One potential neuroprotective agent, dopamine (DA), is a key neuromodulator found throughout the body and within the retina, where it is released by dopaminergic amacrine cells. Diabetic animals have DA deficiencies in the retina (13), brain (19), and kidneys (20). When diabetic rodents are treated with levodopa (L-DOPA), a precursor to DA that crosses the blood-brain and blood-retina barriers, DA levels as well as early OP delays to dim-flash stimuli are restored (13).…”

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension

“…Our previous study showed that LPS exposure during pregnancy leads to impaired renal sodium excretion and hypertension in the offspring attributable to oxidative stress, caused by decreased antioxidant capacity, resulting in the accumulation of reactive oxygen species (ROS) in the kidney. 8 To determine the oxidative stress level in the rats with transgenerational inherited hypertension induced by PLPS exposure, we measured the serum levels of malondialdehyde, a lipid peroxidation product used as an indicator of oxidative stress in the whole body, 31 in F0 to F3 control and PLPS offspring. The serum malondialdehyde levels, measured by ELISA, were significantly increased in F0 and F1 PLPS offspring compared with control rats but decreased to control levels in the F2 and F3 offspring (Figure 5A1).…”

Effect of D4 Dopamine Receptor on Na+-K+-ATPase Activity in Renal Proximal Tubule Cells

“…[6][7][8][9][10][11]14,20,[30][31][32] Our previous studies and those of others have shown that activation of dopamine D 1 -like receptors (D 1 and/or D 5 receptors) inhibits NKA activity in RPT cells. [6][7][8][9][10][11]14,20,[30][31][32][33][34] However, the role of D 4 receptor activation in regulating renal NKA activity remains unclear. The present study showed that activation of D 4 receptors in WKY RPT cells inhibits NKA activity in a dose-and time-dependent manner.…”