IntroductionThe renin-angiotensin system is a regulatory cascade that plays an essential role in the regulation of blood pressure, electrolyte, and volume homeostasis. The first and rate-limiting component of this cascade is renin, a protease synthesized and secreted predominantly by the juxtaglomerular (JG) apparatus in the nephron. Renin cleaves angiotensin I (Ang I) from liver-derived angiotensinogen, which is then converted to Ang II by the angiotensin-converting enzyme. Ang II, through binding to its receptors, exerts diverse actions that affect the electrolyte, volume, and blood pressure homeostasis (1). Inappropriate stimulation of the renin-angiotensin system has been associated with hypertension, heart attack, and stroke.The renin-producing granulated cells are mainly located in the afferent glomerular arterioles in the kidney (2). It is well established that renin secretion is regulated by renal perfusion pressure, renal sympathetic nerve activity, and tubular sodium load (1, 2). Renin secretion is stimulated by factors such as prostaglandins, NO, and adrenomedullin, and inhibited by other factors, including Ang II (feedback), endothelin, vasopressin, and adenosine (1, 2). Stimulation of renin secretion is often mediated by an increase in intracellular cAMP and is accompanied by increases in renin gene transcription (3). In the renin gene promoter, several cAMP response elements have been identified. Recently, steroid hormone receptors LXRα and RAR/RXR complex, transcriptional factors CREB/CREM and USF1/USF2, and HOX gene family members have been found to be involved in the activation of murine renin gene transcription (4-7).Vitamin D is a primary regulator of calcium homeostasis. Genetic inactivation of either the vitamin D receptor (VDR), a member of the nuclear receptor superfamily that mediates the action of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], or 25-hydroxyvitamin D 3 1α-hydroxylase, the rate-limiting enzyme for the biosynthesis of 1,25(OH) 2 D 3 , results in impaired calcium homeostasis, leading to hypocalcemia, secondary hyperparathyroidism, and rickets (8-11). However, the wide tissue distribution of VDR suggests that the vitamin D endocrine system has additional physiological functions beyond calcium homeostasis. Indeed, vitamin D and VDR have been shown to play important roles in the immune system, cardiovascular system, reproductive system, and hair growth. Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and ...

IntroductionThe renin-angiotensin system is a regulatory cascade that plays an essential role in the regulation of blood pressure, electrolyte, and volume homeostasis. The first and rate-limiting component of this cascade is renin, a protease synthesized and secreted predominantly by the juxtaglomerular (JG) apparatus in the nephron. Renin cleaves angiotensin I (Ang I) from liver-derived angiotensinogen, which is then converted to Ang II by the angiotensin-converting enzyme. Ang II, through binding to its receptors, exerts diverse actions that affect the electrolyte, volume, and blood pressure homeostasis (1). Inappropriate stimulation of the renin-angiotensin system has been associated with hypertension, heart attack, and stroke.The renin-producing granulated cells are mainly located in the afferent glomerular arterioles in the kidney (2). It is well established that renin secretion is regulated by renal perfusion pressure, renal sympathetic nerve activity, and tubular sodium load (1, 2). Renin secretion is stimulated by factors such as prostaglandins, NO, and adrenomedullin, and inhibited by other factors, including Ang II (feedback), endothelin, vasopressin, and adenosine (1, 2). Stimulation of renin secretion is often mediated by an increase in intracellular cAMP and is accompanied by increases in renin gene transcription (3). In the renin gene promoter, several cAMP response elements have been identified. Recently, steroid hormone receptors LXRα and RAR/RXR complex, transcriptional factors CREB/CREM and USF1/USF2, and HOX gene family members have been found to be involved in the activation of murine renin gene transcription (4-7).Vitamin D is a primary regulator of calcium homeostasis. Genetic inactivation of either the vitamin D receptor (VDR), a member of the nuclear receptor superfamily that mediates the action of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], or 25-hydroxyvitamin D 3 1α-hydroxylase, the rate-limiting enzyme for the biosynthesis of 1,25(OH) 2 D 3 , results in impaired calcium homeostasis, leading to hypocalcemia, secondary hyperparathyroidism, and rickets (8-11). However, the wide tissue distribution of VDR suggests that the vitamin D endocrine system has additional physiological functions beyond calcium homeostasis. Indeed, vitamin D and VDR have been shown to play important roles in the immune system, cardiovascular system, reproductive system, and hair growth. Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and ...

Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho–PI3K–Akt1–BAD signaling network.

Previously, we showed that vitamin D receptor gene knockout leads to hyperreninemia independent of calcium metabolism; however, the contribution of parathyroid hormone to renin upregulation remained unclear. Here we separated the role of vitamin D and parathyroid hormone in the regulation of renin expression in vivo by generating transgenic mice that overexpressed the human vitamin D receptor in renin-producing cells using the 4.1 kb Ren-1c gene promoter. Targeting of human vitamin D receptor to the juxtaglomerular cells of the mice was confirmed by immunohistochemistry. Renal renin mRNA levels and plasma renin activity were decreased in these transgenic mice by about 50% and 30%, respectively, with no significant change in blood pressure, calcium, or parathyroid hormone levels. Moreover using vitamin D receptor knockout mice, we found that expression of the human receptor in their juxtaglomerular cells reduced renin expression in these mice without affecting calcium or parathyroid hormone status. Our study shows that suppression of renin expression by 1,25-dihydroxyvitamin D in vivo is independent of parathyroid hormone and calcium.

Purpose: We conducted a Phase II clinical trial with randomized patients to determine whether autologous formalin-fixed tumor vaccine (AFTV) protects against postsurgical recurrence of hepatocellular carcinoma (HCC).Experimental Design: Forty-one patients with HCC who had undergone curative resection were randomly allocated to the vaccine treatment (n ‫؍‬ 19) or no adjuvant control group (n ‫؍‬ 22). Three intradermal vaccinations were administered at 2-week intervals beginning 4 -6 weeks after hepatic resection. A delayed-type hypersensitivity test was performed before and after vaccination. Primary and secondary end points are recurrence-free survival and overall survival, respectively. Observation continued until the majority of surviving patients had lived >12 months after the curative resection.Results: In a median follow-up of 15 months, the risk of recurrence in vaccinated patients was reduced by 81% (95% confidence interval, 33-95%; P ‫؍‬ 0.003). Vaccination significantly prolonged the time to first recurrence (P ‫؍‬ 0.003) and improved recurrence-free survival (P ‫؍‬ 0.003) and overall survival rates (P ‫؍‬ 0.01). AFTV played a significant role in preventing recurrence in patients with small tumors. Adverse effects were limited to grade 1 or 2 skin toxicities such as erythema, dry desquamation, and pruritus.Conclusions: AFTV therapy is a safe, feasible, and effective treatment for preventing postoperational recurrence of HCC. Patients with low tumor burdens benefit from the treatment. This treatment should be advanced to a largescale randomized trial.

Although vitamin D has been implicated in cardiovascular protection, few studies have addressed the role of vitamin D receptor (VDR) in atherosclerosis. Here we investigate the effect of inactivation of the VDR signaling on atherogenesis and the antiatherosclerotic mechanism of vitamin D. Low density lipoprotein receptor (LDLR)(-/-)/VDR(-/-) mice exhibited site-specific accelerated atherogenesis, accompanied by increases in adhesion molecules and proinflammatory cytokines in the aorta and cholesterol influx in macrophages. Macrophages showed marked renin up-regulation in the absence of VDR, and inhibition of renin by aliskiren reduced atherosclerosis in LDLR(-/-)/VDR(-/-) mice, suggesting that the renin-angiotensin system (RAS) promotes atherosclerosis in the absence of VDR. LDLR(-/-) mice receiving LDLR(-/-)/VDR(-/-) BMT developed larger lesions than LDLR(-/-) BMT controls. Moreover, LDLR(-/-) mice receiving Rag-1(-/-)/VDR(-/-) BMT, which were unable to generate functional T and B lymphocytes, still had more severe atherosclerosis than Rag-1(-/-) BMT controls, suggesting a critical role of macrophage VDR signaling in atherosclerotic suppression. Aliskiren treatment eliminated the difference in lesions between Rag-1(-/-)/VDR(-/-) BMT and Rag-1(-/-) BMT recipients, indicating that local RAS activation in macrophages contributes to the enhanced atherogenesis seen in Rag-1(-/-)/VDR(-/-) BMT mice. Taken together, these observations provide evidence that macrophage VDR signaling, in part by suppressing the local RAS, inhibits atherosclerosis in mice.

In the general US population, serum 25-hydroxyvitamin D levels are inversely associated with several cardiovascular risk factors, including hypertension, diabetes, obesity, and hyperlipidemia.1 Low levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D [1,25(OH) 2 D 3 ] are associated with congestive heart failure and an increased rate of all-cause and cardiovascular mortality. 2-4Prospective studies have demonstrated an association between low serum 25-hydroxyvitamin D levels and increased risk of incident cardiovascular disease and myocardial infarction. 5,6 In patients with chronic kidney disease, where cardiovascular disease is the leading cause of death, therapy with activated vitamin D is associated with a reduction in mortality. 7,8 Vitamin D's cardiovascular effects may be mediated in part by regulation of the renin-angiotensin system (RAS).9,10 1,25(OH) 2 D 3 and its analogs inhibit renin expression in vivo 11 and an inverse correlation has been reported between levels of serum 1,25(OH) 2 D 3 and plasma renin activity in humans.12,13 A therapeutic effect of vitamin D in humans, however, has not been conclusively demonstrated. Pharmacological inhibition of the RAS with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) is commonly

MAS) and 10 typically developing participants (four males, six females; mean age 10y 3mo, SD 2y 7mo, range 7-15y). Spasticity and catch angle were evaluated using joint position, resistance torque, and torque rate at velocities of 90°, 180°, and 270°per second, controlled using real-time audio-visual feedback. Biomechanically, elbow range of motion (ROM), stiffness, and energy loss were determined during slow movement (30°⁄ s) and under controlled terminal torque.RESULTS Compared with typically developing children, children with CP showed higher reflexmediated torque (p<0.001) and the torque increased more rapidly with increasing velocity (p<0.001). Catch angle was dependent on velocity and occurred later with increasing velocity (p=0.005). Children with CP showed smaller ROM (p<0.05), greater stiffness (p<0.001), and more energy loss (p=0.003).