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Glaucoma is the leading cause of blindness in Japan, and an alternative treatment to lowering intraocular pressure (IOP) is required to manage this disease. We found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) were increased in retinal ganglion cells (RGCs) and retinal Müller glia in normal tension glaucoma (NTG) model mouse. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions, especially in retinal Müller glia. Treatment with candesartan was effective for RGC protection without affecting IOP. These results suggest that the renin-angiotensin system is involved in the innate immune responses in both neural and glial cells, and AT1-R antagonist may exert IOP-independent neuroprotective effects.

Kidney is an energy-consuming organ and its function deteriorates according as aging. Various mechanisms for cellular senescence and organ aging have an impact on the initiation and progression of CKD, which includes telomere attrition, genomic instability, stem cell exhaustion, mitochondrial dysfunction, impaired nutrient signaling, inactivation of Sirtuin or Klotho-mediated pathway and renin-angiotensin system activation. Interventions in these pathways have provided therapeutic strategy against CKD. On the other hand, renal dys- function, in turn, affects human aging process. Because of this close relationship between human aging process and CKD, aging phenotype, such as frailty can be used as a clinical marker of the prognosis of CKD as well as of other age-related diseases including cardio- vascular disease and type II diabetes. Amelioration of this aging phenotype can provide a novel therapeutic strategy against CKD for the purpose of providing CKD patients with suc- cessful aging.

Blood pressure is controlled by baroreceptor reflex and pressure natriuresis which consists of renal blood flow autoregulation and tubuloglomerular feedback loop. The tissue renin-angiotensin system in the kidneys contributes to the sensitivity of pressure natriuresis, and the sympathetic nervous activity further affects the tissue renin-angiotensin system in the kidneys and baroreceptor reflex. Moreover, the brain renin-angiotensin system enhances the sympathetic nervous activity. It is therefore likely that the brain renin-angiotensin system plays a pivotal role in the pathogenesis of primary hypertension. Recent studies showed that the expression levels of (pro) renin receptor increase in the brain of hypertensive rats, and that knocking down (pro) renin receptor expression leads to normalization of blood pressure. Because the (pro)renin receptor is known to regulate the tissue renin-angiotensin system, brain (pro) renin receptor may be a novel therapeutic target for primary hypertension.

Hypertension is recognized as a significant risk factor for cardiovascular complications and associated with mortality. Many antihypertensive drugs have been developed in last decades and several placebo-controlled trials have demonstrated that lowering blood pressure with drug treatment reduces the incidence of cardiovascular diseases including stroke, coronary disease and renal injury. However, blood pressure control remains insufficient in many hypertensive patients who are treated with antihypertensive drugs. In addition, several clinical trials failed to demonstrate that different classes of antihypertensive agents vary in their capacity to decrease cardiovascular and renal disease, independent of their ability to lower blood pressure. Thus, further efforts will be needed to develop the new antihypertensive agent in order to prevent cardiovascular disease outcomes or death. This article provides an overview of currently available data on development trends for antihypertensive drug. In particular, we will focus on the new drugs related to the renin-angiotensin-aldosterone system. We will not discuss novel interventional approaches such as renal denervation, carotid body ablation and arteriovenous fistula placement.

It is well known that there are differences in prevalence and progression of kidney disease between men and women. Several experimental models of chronic kidney disease (CKD) have revealed the different effects of gender on the course and responses to salt and vascular modulating substances. The prominent differences between men and women are attributable to sex hormones. Estrogen has profound effects on the renin-angiotensin system, producing alteration of renal function and structures. In this article, first, the differences in renal structure and function are introduced and then the effects of estrogen on renal hemodynamics and progression of renal diseases will be discussed.

Hypertension is the largest risk factor for cardiovascular disease (CVD), and the most common life-style related disease in Japan. Hypertension is, overall, a male-dominant disease, however its impact on CVD in female grows markedly after menopause. The alteration in estrogen/androgen balance causes endothelial dysfunction, obesity, sympathetic activation, renin-angiotensin-aldosterone system activation, salt sensitivity and oxidative stress. These mechanisms enhance the elevation of systemic blood pressure and get caught in a vicious circle in female hypertension.

Hypertension, osteoporosis and vascular calcification are major diseases in the recent aging society and may share the same backgrounds genetically and environmentally. As treatments to prevent aging-related diseases simultaneously are desirable, we investigate common backgrounds underling these diseases. Renin- angiotensin system, which causes high blood pressure, is found to be involved in bone metabolism. Angiotensin II has been shown to accelerate osteoporosis through RANKL up-regulation in osteoblast. RANKL, in turn, contributes to vascular calcification by regulating bone morphogenetic protein-2 and MGP expression, as well as bone-related proteins. Angiotensin type 1 receptor blockers (ARBs) ameliorate osteoporosis and vascular calcification beyond their blood pressure lowering effects. These pleiotropic effects of antihypertensive drugs such as ARBs might benefit especially hypertensive postmenopausal women.

Rasilez(®) tablets (RTs) contain the active ingredient aliskiren, which is a direct renin inhibitor of the renin-angiotensin system and used for the treatment of hypertension. We examined the influence of temperature and humidity on the physico-pharmaceutical characteristics (mass, volume, hardness, elution) of RTs. The RTs were preserved under conditions in which the temperature and humidity were altered using the second-order spherical composite experimental design for multi-objective problems. The characteristics of RTs were influenced more by the humidity than temperature, and differed markedly with over 55% relative humidity (RH). The mass and volume were increased with increasing humidity, and the tablets swelled. The hardness after vacuum-drying of the tablets, which preserved moisture conditions, was increased. Semitransparent particles were observed in the cross-section of the drying tablets in which aliskiren crystal forms were changed to amorphous forms. The mean dissolution time (MDT) of tablets was reduced with increasing humidity. The critical relative humidity (CRH) of the tablets was 36.1%RH at 30°C. These results suggest that RTs, on moisture absorption, showed changes in not their appearance and hardness, but also in crystal forms and the elution characteristics of aliskiren.

The renin-angiotensin-aldosterone system(RAAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease and chronic renal failure. In this cascade, the ACE/Ang II/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation and fibrosis. Recently the ACE2/Ang(1-7)/Mas receptor axis has been recognized as a negative regulator of the RAAS. ACE2 metabolizes Ang II into Ang(1-7), which has opposite properties of Ang II through Mas receptor activation. Both animal and human studies provide strong evidence that the ACE2/Ang(1-7)/Mas receptor axis is protective for end-organ damage. Therefore, the ACE2/Ang(1-7)/Mas receptor axis could be a therapeutic target for coronary artery disease and chronic renal failure.

The renin-angiotensin system (RAS) plays a central role in the control of systemic blood pressure. Since the 1950s, both laboratory and clinical studies have been performed to test the efficacy of vaccines against the RAS for the management of hypertension. Although initial studies using renin vaccines and angiotensin I vaccines were unsuccessful, a recent phase IIa study has shown that vaccination against angiotensin II is effective for the treatment of patients with essential hypertension. Results from animal studies have also suggested that vaccination against the AT1 receptor may be effective not only for lowering blood pressure, but also for the prevention of hypertensive end-organ damage. In the future, the RAS may be an important target for the development of vaccines not only for the treatment, but also for the prevention of hypertension and hypertensive complications.

The (pro)renin receptor was first identified as a 350-amino acid protein with a single transmembrane domain. This receptor binds to prorenin to mediate its dual functions: activation of ERK1/2 independently from angiotensin II generation and induction of full enzymatic activity to initiate angiotensin II-dependent effects. (Pro) renin receptor has recently been shown to undergo intracellular processing, such that it exists in three different molecular forms. These include the full-length (pro)renin receptor, truncated amino-terminal soluble fragment, and carboxy-terminal fragment containing an accessory protein of the vacuolar-type H(+)-ATPase. Their exact distributions and existing molecular forms remain to be determined.

Angiotensin II (AII), the biologically active component of renin-angiotensin system (RAS), acts through two receptor subtypes, the AT1 and AT2 receptor. All classic physiological effects of AII, such as vasoconstriction, aldosterone and vasopressin release, sodium and water retention and sympathetic facilitation, are mediated by the AT1 receptor. The majority of pilot studies demonstrated the renoprotective effect of RAS blockers via antihypertensive, antiproteinuric, antifibrotic action. In order to establish whether RAS blocker causes antiproteinuric effects or long-term renoprotection in the non-diabetic nephrotic disease, larger prospective, randomized controlled trials are required in the future.

Antihypertensive treatment is essential to prevention and inhibition of cardiovascular accidents and nephropathy in diabetic patients. Studies have shown that inhibition of the renin-angiotensin system(RAS) exerts beneficial effects beyond its blood pressure-lowing action. In patients with renal dysfunction, RAS inhibition occasionally causes further decline in renal function and hyperkalemia. Because of this, general physicians may hesitate to prescribe RAS inhibitors to patients with renal dysfunction. However, clinical studies have clearly shown that RAS inhibition is particularly beneficial in those patients. This article discusses the conditions associated with RAS inhibition-induced decline in renal function and measures to take against them. In addition, combination therapy with other classes of anti-hypertensives according to renal function and proteinuria is discussed.

We report a rare case of Gitelman's syndrome (GS) presenting with the hypokalemic periodic paralysis. A 27-year-old man was admitted to our hospital because of transient weakness of the limbs. Past history was unremarkable, including the delivery and early developmental milestones, except for a transient limb weakness 7 times since the age of 15 years. The blood pressure was 140/90 mmHg. The physical examinations were unremarkable. Neurologically, the patient was fully oriented. The cranial-nerve functions were intact. Manual muscle tests revealed 1/5 weakness in his neck and extremities. Sensation was normal in all modalities. The deep tendon reflexes were present but decreased mildly. Laboratory tests showed hypokalemia (1.9 mEq/l), hypomagnesemia (1.8 mEq/l), and hypocalciuria (40.0 mg/dl). Plasma rennin activity and aldosterone concentration were elevated. The molar ratio of urinary calcium/creatinine was 0.11 (< 0.2). Arterial blood gas showed mild metabolic alkalosis with respiratory compensation. Because of these data, the diagnosis of GS was made. Gene mutations in the renal thiazide sensitive Na-Cl cotransporter (TSC) have already been shown to cause GS. Although we searched for gene mutation of TSC, none of 25 mutations in 18 out of 26 exons which had been previously reported were found. This is the first report of Gitelman's syndrome presenting with the hypokalemic periodic paralysis in Japan.

Although hyponatremia has been known to occur in patients with severe spinal cord injury with highly incidence, its mechanism has not been understood well. We examined a 64-year-old patient with severe hyponatremia after spinal cord injury by sequential measuring of the factors affecting water-electrolyte balance, such as antidiuretic hormone, renin, angiotensin II, atrial natriuretic peptide, and brain natriuretic peptide. The patient showed severe hypotension due to dysfunction of the sympathetic nerve. The hyponatremia gradually resolved with the improvement of sympathetic nerve function. According to those results, the sympathetic nerve dysfunction was thought to correlate with the hyponatremia, and it was suggested that the unknown sympathetic regulation of water-electrolyte balance existed.

Angiotensin II(AII) accelerates the progress of cardiovascular diseases. This was proved by the fact that the blockade of renin-angiotensin system provided clinical benefits for patients with cardiovascular diseases. This review focuses on the differences between AT1-receptor antagonist and ACE inhibitor in basic and clinical aspects. Beside decreased AII concentration, increased tissue bradykinin concentration may contribute to the beneficial effect of ACE inhibitor, on the other hand, this increases the rate of cough to decrease the compliance. Increased AII concentration by AII receptor antagonist may antagonize the binding of the drug as well as stimulate AT2 receptor subtype. ACE inhibitor can not block the effect of non-ACE AII formation, but AII receptor does. These differences should be considered for their clinical use.

Nonpeptide angiotensin II type 1-receptor antagonists, AT1 receptor antagonists are newly developed and useful drugs for hypertension and congestive heart failure. In Japan, the efficacy and safety of losartan and candesartan cilexetil in patients with essential hypertension have been evaluated by the double-blind, parallel group-comparison study using enalapril as control drug. Both trials revealed that these drugs showed a hypotensive effect comparable to that of enalapril with a high safety since the adverse drug reaction of cough was recognized in very few patients. Furthermore, a recent randomised trial of losartan versus captopril in patients over 65 with heart failure, evaluation of losartan in the elderly study (ELITE), showed that losartan was associated with a lower mortality than that found with captopril. Further studies will clarify differences in protection of cardiovascular system with a long-term treatment between AT1, receptor antagonists and angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme (ACE) inhibitors now have an accepted place in the treatment of hypertension and congestive heart failure. With the discovery and development of captopril, several other ACE inhibitors have been synthesized and introduced for clinical use. All ACE inhibitors bind to zinc ions located in the active site of the ACE molecule. ACE inhibitors can be classified according to the ligand of the zinc ion of ACE, into 3 different structural types: (1) the first type such as captopril has a sulphhydryl moiety as the ligand; (2) the second type such as enalapril uses a carboxyl moiety as the ligand; (3) the third type such as fosinopril uses neither a sulphhydryl nor carboxyl group, but a phosphinic acid as the zinc binding moiety. ACE inhibitors can also be classified according to the excretion route of their active moiety, into 2 different excretion route types:(1) excreated mainly through the kidney such as captopril, enalaprilat, lisinopril, benazeprilat, imdaprilat, trandraprilat, etc.; (2) excreated both in the bile and urine such as fosinoprilat, temocaprilat, zofenoprilat etc. ACE inhibitors have clinically beneficial effects not only for patients with either hypertension or congestive heart failure, but also can be used to prevent the progression of renal dysfunction induced by hypertension and diabetes mellitus.

Among the factors, which may influence on the uric acid metabolism, the excess or deficiency of some hormones apparently induces the abnormal serum uric acid level. We described hyperuricemia and hypouricemia associated with endocrine disorders. Hyperuricemia due to the increased production of uric acid is observed in myopathy associated with hypothyroidism, hyperthyroidism or hypoparathyroidism. Hyperuricemia due to the decreased renal uric acid clearance is associated with hypopituitarism, hypothyroidism, hyperparathyroidism, central diabetes insipidus, nephrogenic diabetes insipidus, Bartter syndrome, and diabetic ketoacidosis. Hypouricemia due to the increased renal uric acid clearance is associated with hypoparathyroidism, primary aldosteronism and inappropriate secretion of antidiuretic hormone (SIADH).

Endocrine disorders associated with diabetes mellitus are described. When blood glucose control deteriorates, observed endocrine abnormalities are as follows. 1) Blood GH levels increase. This elevation is small but enough to disturb insulin secretion and glucose metabolism. Plama insulin-like growth factor-1 levels decrease in spite of their strong relation with diabetic retinopathy. 2) Blood thyroid hormones show the similarity with low T3 syndrome. 3) Hyporeninemic hypoaldosteronism occurs especially with patients who have hypertension or moderate diabetic complications. 4) Plasma pancreatic glucagon levels are elevated. Amino acids induce hypersecretion but hypoglycemia fails to response normally. Glucose administration shows impaired inhibition or paradoxical hypersecretion. 5) Other plasma levels of pancreatic hormones such as gastrin, secretin, motilin and somatostatin are usually elevated.