Gilbert M. Eisner

Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Essential hypertension has a heritability as high as 30–50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4γ, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4γA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.

Renal Dopamine Receptors in Health and Hypertension

During the past decade, it has become evident that dopamine plays an important role in the regulation of renal function and blood pressure. Dopamine exerts its actions via a class of cell-surface receptors coupled to G-proteins that belong to the rhodopsin family. Dopamine receptors have been classified into two families based on pharmacologic and molecular cloning studies. In mammals, two D1-like receptors that have been cloned, the D1 and D5 receptors (known as D1A and D1B, respectively, in rodents), are linked to stimulation of adenylyl cyclase. Three D2-like receptors that have been cloned (D2, D3, and D4) are linked to inhibition of adenylyl cyclase and Ca2+ channels and stimulation of K+ channels. All the mammalian dopamine receptors, initially cloned from the brain, have been found to be expressed outside the central nervous system, in such sites as the adrenal gland, blood vessels, carotid body, intestines, heart, parathyroid gland, and the kidney and urinary tract. Dopamine receptor subtypes are differentially expressed along the nephron, where they regulate renal hemodynamics and electrolyte and water transport, as well as renin secretion. The ability of renal proximal tubules to produce dopamine and the presence of receptors in these tubules suggest that dopamine can act in an autocrine or paracrine fashion; this action becomes most evident during extracellular fluid volume expansion. This renal autocrine/paracrine function is lost in essential hypertension and in some animal models of genetic hypertension; disruption of the D1 or D3 receptor produces hypertension in mice. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to the hypertension. The molecular basis for the dopaminergic dysfunction in hypertension is not known, but may involve an abnormal post-translational modification of the dopamine receptor.

Role of the D1A dopamine receptor in the pathogenesis of genetic hypertension.

Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na+/H+ exchanger [NHE] and Na+/K+ATPase activity) by dopamine. To determine if impaired D1 receptor regulation of NHE in proximal tubules is related to hypertension, studies were performed in a F2 generation from female Wistar Kyoto (WKY) and male SHR crosses. A D1 agonist, SKF 81297, inhibited (37.6 +/- 4.7%) NHE activity in brush border membranes of normotensive F2s (systolic blood pressure < 140 mm Hg, n = 7) but not in hypertensive F2s (n = 21). Furthermore, a D1 agonist, SKF 38393, when infused into the renal artery, dose dependently increased sodium excretion in normotensive F2s (n = 3) without altering renal blood flow but was inactive in hypertensive F2s (n = 21). Since the major D1 receptor gene expressed in renal proximal tubules is the D1A subtype, we determined the importance of this gene in the control of blood pressure in mice lacking functional D1A receptors. Systolic blood pressure was greater in homozygous (n = 6) and heterozygous (n = 5) mice compared to normal sex matched litter mate controls (n = 12); moreover, the mice lacking one or both D1A alleles developed diastolic hypertension. The cosegregation with hypertension of an impaired D1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D1A alleles suggest a causal relationship of the D1A receptor gene with hypertension.

Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension.

Since dopamine receptors are important in the regulation of renal and cardiovascular function, we studied the cardiovascular consequences of the disruption of the D3 receptor, a member of the family of D2-like receptors, expressed in renal proximal tubules and juxtaglomerular cells. Systolic and diastolic blood pressures were higher (approximately 20 mmHg) in heterozygous and homozygous than in wild-type mice. An acute saline load increased urine flow rate and sodium excretion to a similar extent in wild-type and heterozygous mice but the increase was attenuated in homozygous mice. Renal renin activity was much greater in homozygous than in wild-type mice; values for heterozygous mice were intermediate. Blockade of angiotensin II subtype-1 receptors decreased systolic blood pressure for a longer duration in mutant than in wild-type mice. Thus, disruption of the D3 receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension.

Short Telomeres and Prognosis of Hypertension in a Chinese Population

Aging is a major risk factor for hypertension and cardiovascular disease. Accumulating evidence suggests that telomere length is a marker for biological aging of the cardiovascular system. Telomere length is determined by genetic and environmental factors. Studies in different racial populations are required to determine the prognostic value of telomere length in hypertension and cardiovascular diseases. The main objective of this study was to investigate the association between leukocyte telomere length and the risk and prognosis of hypertension in a Chinese population. The relative telomere length of leukocytes was determined by a quantitative PCR-based method in 767 subjects: 379 healthy controls and 388 hypertensive patients, ages 30 to 80 years. The median telomere length ratio, 0.57 (interquartile range: 0.48 to 0.72), was shorter in hypertensive than in healthy normotensive subjects (0.67; interquartile range: 0.53 to 0.93; P<0.001). After 5 years of follow-up, subjects with shorter telomeres were at a higher risk of developing coronary artery disease than individuals with longer telomeres (odds ratio: 3.315; 95% CI: 1.662 to 6.609; P<0.001). Multivariate analysis showed that short telomere length and hypertension were independent risk factors for developing coronary artery disease. Our data suggest that mean leukocyte telomere length is a potential predictor of coronary artery disease and support the hypothesis that differences in biological aging can contribute to the risk and variability of developing hypertension and cardiovascular diseases.

Perturbation of D1 Dopamine and AT1 Receptor Interaction in Spontaneously Hypertensive Rats

Abstract—The dopaminergic and renin-angiotensin systems interact to regulate blood pressure. Because this interaction may be perturbed in genetic hypertension, we studied D1 dopamine and AT1 angiotensin receptors in immortalized renal proximal tubule (RPT) and A10 aortic vascular smooth muscle cells. In normotensive Wistar-Kyoto (WKY) rats, the D1-like agonist fenoldopam increased D1 receptors but decreased AT1 receptors. These effects were blocked by the D1-like antagonist SCH 23390 (10−7 mol/L per 24 hours). In spontaneously hypertensive rat (SHR) RPT cells, fenoldopam also decreased AT1 receptors but no longer stimulated D1 receptor expression. Basal levels of AT1/D1 receptor coimmunoprecipitation were greater in WKY RPT cells (29±2 density units, DU) than in SHR RPT cells (21±2 DU, n=7 per group, P <0.05). The coimmunoprecipitation of D1 and AT1 receptors was increased by fenoldopam (10−7 mol/L per 24 hours) in WKY RPT cells but decreased in SHR RPT cells. The effects of fenoldopam in RPT cells from WKY rats were similar in aortic vascular smooth muscle cells from normotensive BD IX rats, that is, fenoldopam decreased AT1 receptors and increased D1 receptors. Our studies show differential regulation of the expression of D1 and AT1 receptors in RPT cells from WKY and SHR. This regulation and D1/AT1 receptor interaction are different in RPT cells of WKY and SHR. An altered interaction of D1 and AT1 receptors may play a role in the impaired sodium excretion and enhanced vasoconstriction in hypertension.

Role of dopamine receptors in the kidney in the regulation of blood pressure.

Regulation by dopamine of cardiovascular function, renal function and systemic blood pressure regulation is multifaceted. Each of the five dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. The D1, D3, and D4 receptors interact with the renin-angiotensin system, while the D2 and D5 receptors interact with the sympathetic nervous system to regulate blood pressure.

The dopaminergic system in hypertension

Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin-angiotensin and sympathetic nervous systems. Dopamine receptors are classified into D(1)-like (D(1) and D(5)) and D(2)-like (D(2), D(3) and D(4)) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. This review summarizes the physiology of the different dopamine receptors in the regulation of blood pressure, and the relationship between dopamine receptor subtypes and hypertension.

Activation of D3 Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells

The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D3 dopamine receptor gene in mice produces renin-dependent hypertension. In rats, D2-like receptors reduce angiotensin II binding sites in renal proximal tubules (RPTs). Because the major D2-like receptor in RPTs is the D3 receptor, we examined whether D3 receptors regulate angiotensin II type 1 (AT1) receptors in rat RPT cells. The effect of D3 receptors on AT1 receptors was studied in vitro and in vivo. The D3 receptor agonist PD128907 decreased AT1 receptor protein and mRNA in WKY RPT cells and increased it in SHR cells. PD128907 increased D3 receptors in WKY cells but had no effect in SHR cells. D3/AT1 receptors colocalized in RPT cells; D3 receptor stimulation decreased the percent amount of D3 receptors that coimmunoprecipitated with AT1 receptors to a greater extent in WKY than in SHR cells. However, D3 receptor stimulation did not change the percent amount of AT1 receptors that coimmunoprecipitated with D3 receptors in WKY cells and markedly decreased the coimmunoprecipitation in SHR cells. The D3 receptor also regulated the AT1 receptor in vivo because AT1 receptor expression was increased in kidneys of D3 receptor–null mice compared with wild type littermates. D3 receptors may regulate AT1 receptor function by direct interaction with and regulation of AT1 receptor expression. One mechanism of hypertension may be related to increased renal expression of AT1 receptors due decreased D3 receptor regulation.