Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.The worldwide prevalence of obesity and associated cardiometabolic diseases have increased dramatically in the past 2-3 decades, rapidly becoming major challenges to the health care systems of most industrialized countries. Current estimates indicate that Ͼ1 billion people in the world are overweight or obese (1). In the United States, at least 65% of adults are overweight, and approximately one-third of adults are obese with a body mass index (defined as kilograms of weight/m 2 of height) of Ͼ30 (2). In children, the prevalence of obesity has also risen rapidly in parallel with increasing obesity in adults; a recent report indicates that 18.4% of 4-year-old children in the United States are obese, with significantly higher rates of obesity in Hispanic, black, and Native American children (3).Associated with obesity is a cascade of metabolic and cardiovascular disorders, including hypertension, a primary mediator of obesity-induced cardiovascular disease. Population studies show that excess weight gain predicts future development of hypertension, and the relationship between body mass index and blood pressure (BP) 2 appears to be nearly linear in diverse populations throughout the world (4). Some studies suggest that excess weight gain may account for 65-75% of human essential hypertension (5). Moreover, clinical studies indicate that weight loss is effective in primary prevention of hypertension and in reducing BP in most hypertensive subjects (6).Although the importance of obesity as a major cause of essential hypertension is well established, the physiological and molecular mechanisms that mediate the BP effects of excess weight gain are only beginning to be elucidated. Excess Weight Gain Increases Renal SodiumReabsorption and Impairs Pressure Natriuresis Table 1 summarizes some of the changes in cardiovascular, neurohormonal, and renal function that occur in obese humans and experimental animals (4,7,8). Notable changes, in addition to increased BP, include increases in cardiac output and heart rate as well as activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). Rapid weight gain also stimulates renal tubular sodium reabsorption, and obese subjects require higher than normal BP to maintain balance between intake and renal excretion of sodium, indicating impaired renal pressure natriuresis (4).Three factors are especially important in increasing re...

Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P) of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.

Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.

20-Hydroxyeicosatetraenoic acid (20-HETE) plays an important role in the regulation of renal tubular and vascular function and a deficiency in the renal formation of 20-HETE has been linked to the development of hypertension. The cytochrome P450 4F2 (CYP4F2) gene encodes for the major CYP enzyme responsible for the synthesis of 20-HETE in the human kidney. We screened two human sampling panels (African and European Americans: n = 24 and 23 individuals, respectively) using PCR and DNA resequencing to identify informative SNPs in the coding region of the CYP4F2 gene. Two nonsynonymous SNPs that lead to amino acid changes at position 12 (W12G) and 433 (V433M), were identified. Both of these variants were found to be frequent in both African and European American sampling panels (9-21% minor allele frequency), and the W12G polymorphism exhibited extensive linkage disequilibrium with surrounding SNPs. To determine the functional significance of these mutations on the ability of the CYP4F2 enzyme to metabolize arachidonic acid and leukotriene B(4) (LTB(4)), recombinant baculoviruses containing four different human CYP4F2 variants (i.e., W12/V433, W12/M433, G12/V433, G12/M433) were generated and the proteins were expressed in Sf9 insect cells. The presence of the M433 allele, W12/M433, or G12/M433 decreased 20-HETE production to 56-66% of control. In contrast these variants had no effect on the omega-hydroxylation of LTB(4). These findings are the first to identify a functional variant in the human CYP4F2 gene that alters the production of 20-HETE.

Heme oxygenase (HO) induction has been demonstrated to be beneficial in limiting the extent of cellular damage after ischemia-induced acute renal failure (ARF). Because increased HO activity is associated with the production of carbon monoxide (CO) as well as the potent antioxidant bilirubin, it is unclear which of the two is of greater importance in the protective effects of HO induction. The purpose of this study was to determine the protective role of CO alone in ischemia-induced ARF. Bilateral clamping of the renal pedicle for 40 min was associated with a ninefold increase in the levels of plasma creatinine 24 h after reperfusion as compared with normal plasma creatinine levels; however, administration of CO donor compounds tricarbonyldichlororuthenium(II) dimer, ([Ru(CO) 3 Cl 2 ] 2 , 10 mg/kg) or tricarbonylchloro(glycinato)ruthenium(II) ([Ru(CO) 3 Cl(glycinate)], (CORM-3) 1 h before the onset of ischemia significantly decreased the levels of plasma creatinine 24 h after reperfusion as compared with vehicle-treated mice. Surprising, treatment with the CO donors was associated with an increase in HO activity 24 h after ischemia. For determining whether the protective effects of the CO donors were due to CO or HO-1 induction, experiments were performed in which HO was inhibited before administration of the CO donors. Pretreatment with the HO inhibitor had no effect on the level of plasma creatinine 24 h after reperfusion after treatment with the CO donor compounds. These results suggest that CO itself may be protective and limit renal damage in ischemia induced ARF. 16: 950-958, 2005. J Am Soc Nephrol

We tested the hypothesis that the tissue-specific intrarenal renin-angiotensin system (RAS) can participate in the regulation of blood pressure independently of its endocrine counterpart, by generating two transgenic models that differ in their tissue-specific expression of human angiotensinogen (AGT). Human AGT expression was driven by its endogenous promoter in the systemic model and by the kidney androgen-regulated protein promoter in the kidney-specific model. Using molecular, biochemical, and physiological measurements, we demonstrate that human AGT mRNA and protein are restricted to the kidney in the kidney-specific model. Plasma ANG II was elevated in the systemic model but not in the kidney-specific model. Nevertheless, blood pressure was markedly elevated in both the systemic and kidney-specific transgenic mice. Acute administration of the selective ANG II AT-1 receptor antagonist losartan lowered blood pressure in the systemic model but not in the kidney-specific model. These results provide evidence for the potential importance of the intrarenal RAS in blood pressure regulation by showing that expression of AGT specifically in the kidney leads to chronic hypertension independently of the endocrine RAS.

Abstract-The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (Ϫ/Ϫ) and heterozygous (ϩ/Ϫ) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (nϭ5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (Ϫ/Ϫ) mice were severely obese compared with MC4R (ϩ/Ϫ) and WT mice (body weight 48Ϯ1.5 versus 31Ϯ0.6 and 30Ϯ0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (Ϫ/Ϫ) 110Ϯ3 mm Hg; MC4R (ϩ/Ϫ) 109Ϯ2 mm Hg; WT 114Ϯ2 mm Hg), and HR in MC4R (Ϫ/Ϫ) was lower than in WT (604Ϯ5 versus 645Ϯ9 bpm; PϽ0.05) but not different from MC4R (ϩ/Ϫ) (625Ϯ13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (Ϫ/Ϫ) compared with MC4R (ϩ/Ϫ) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (Ϫ/Ϫ) than in MC4R (ϩ/Ϫ) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (Ϫ/Ϫ) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities. Key Words: obesity Ⅲ insulin resistance Ⅲ hypertension, sodium-dependent Ⅲ arterial pressure Ⅲ renin-angiotensin system E vidence from epidemiological, clinical, and experimental studies has consistently demonstrated that obesity is a major cause of essential hypertension. 1-3 Previous studies show that ␣/␤-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain in diet-induced obese animal models, indicating that increased sympathetic nervous system (SNS) activation is an important cause of obesity-induced hypertension. 3,4 However, the mechanisms that link SNS activation to the development of hypertension in obesity are still unclear.One potential mechanism that could link obesity, SNS activation, and hypertension is the hypothalamic proopiomelanocortin (POMC) pathway. Several studies have indicated that the hypothalamic melanocortin system, acting through the melanocortin-3 receptor (MC3R) and MC4R, is a major regulator of energy balance. ␣-Melanocyte-stimulating hormone (␣-MSH), the proteolytic byproduct of the POMC peptide, activates the hypothalamic MC3/4R to suppress appetite and to increase energy expenditure. 5 Recent studies suggest that the hypothalamic melanocortin system may also be important in cardiovascular regulation. For example, acute intracerebroventricular injections of ␣-MSH increase SNS activity to the kidneys, 6 and chronic activation of MC3/4...