Published papers

Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.

Background: The standard treatment for ACTH-independent macronodular adrenal hyperplasia (AIMAH) with overt Cushing's syndrome is bilateral adrenalectomy. Here we show a case of AIMAH who underwent total adrenalectomy on one side and partial adrenalectomy on the other, resulting in the successful debulking of cortisol-secreting adrenal masses and improvement of Cushing's syndrome, yet not necessitating postoperative steroid replacement. Case presentation: A 74-year-old female patient with hypertension, type 2 diabetes and dyslipidemia developed edema of the legs. She visited her primary physician and was found to have lumbar vertebral compression fractures. The blood test and 24-hr urine collection revealed the plasma cortisol levels of 26.1 μg per dL, adrenocorticotropic hormone of 1.1 pg per mL, and urine free cortisol of 340 μg per day. Computed tomographic scan and adrenal scintigraphy confirmed bilateral adrenal nodules with notable tracer uptake. Diagnosis of AIMAH with Cushing's syndrome was made. Laparoscopic partial adrenalectomy, i.e., total removal of the left adrenal gland and partial removal of the right counterpart, was conducted aiming to avert from steroid replacement therapy. After the surgery, blood pressure and glycemic control were markedly improved and maintained for 4 years whilst adrenocortical functions were preserved. Conclusion: Partial adrenalectomy could be an effective therapy in selected cases of AIMAH.

Background: Resistant hypertension is defined as blood pressure that remains above 140/90 mmHg despite the use of three antihypertensive medications of different classes at the maximally tolerated doses, one of which is a diuretic. It is reported that approximately 10% of patients with hypertension have resistant hypertension, but the optimal management of resistant hypertension remains to be unclear. Case presentation: A 56-year-old Japanese woman visited our hospital because she presented high blood pressure of about 170/100 mm Hg even after the treatment by her primary physician. She had hypertension after giving birth at age 26 and her blood pressure was about 170/100 mm Hg. She was suspected of having secondary hypertension and the laboratory and imaging examination were conducted. The functions of the adrenal gland and thyroid were normal, and the renal artery stenosis and chronic kidney disease were excluded. She did not have NSAIDs, oral contraceptives, and herbal products. Although she had been intensively treated for hypertension, she suffered from a brain hemorrhage. Her systolic blood pressure has been still not controlled appropriately by 80 mg of nifedipine, 400 mg of the combination of sacubitril/valsartan, 2.5 mg of esaxerenone, 2 mg of trichlormethiazide, and 9 mg of bisoprolol transdermal patch daily. Conclusion: Because patients with resistant hypertension have a higher risk of stroke, kidney disease, and heart failure, the careful examination and intensive treatment are necessary.

Background: Both primary aldosteronism (PA) and Cushing's syndrome (CS) cause hypertension. It is known that PA can be complicated with CS, but cases with both bilateral PA and unilateral CS are rare. Case presentation: A 65-year-old male patient was treated on 10 mg of amlodipine and 2 mg of doxazosin for hypertension from 6 years ago and his blood pressure was about 150/90 mm Hg on average. Because he gained 10 kg of weight over the last 6 months, he visited his primary physician. He had moon face and central obesity, and his blood examination showed the high concentrations of adrenal hormones, i.e., plasma aldosterone concentration (PAC) was 180 pg/mL and plasma renin activity (PRA) was 0.9 ng/mL/h (aldosterone-renin ratio (ARR) was 200.2), cortisol was 11.1 mcg/dL and adrenocorticotropic hormone was undetectable. The twenty-four-hour urine test showed that the greater secretion of adrenal hormones, i.e., aldosterone was 21.4 mcg/day, free cortisol was 148.5 mcg/day (sodium was 190 mEq/day). The computed tomography scan showed bilateral adrenal tumors (37 mm on the left and 8 mm on the right, respectively). The captopril challenge test, the furosemide stress test, and the 1 mg and 8 mg dexamethasone suppression tests were conducted, and he was diagnosed with both PA and CS. By adrenal scintigraphy using 131I-adosterol, high accumulation was detected in the left adrenal gland, whereas there was no accumulation in the right adrenal gland. Hence, the tumor of the left adrenal gland was likely a cortisol-secreting adrenocortical tumor. Furthermore, super-selective adrenal venous sampling indicated autonomous aldosterone secretion from bilateral adrenal glands. The patient underwent laparoscopic left adrenalectomy and the hypercortisolism was corrected. He lost 10 kg of weight 1 year after the surgery. PA remained as indicated by the blood test showing that PRA was 1.2 ng/mL/h, PAC was 347 pg/mL (ARR was 289.2). He is treated with 5 mg of esaxerenone, and his blood pressure is 130/70 mmHg on average. Conclusion: Adrenal venous sampling was able to determine laterality of PA with coexisting CS.

Background: Primary aldosteronism (PA) has been known to cause organ damage, such as renal and cardiovascular disorders more frequently than essential hypertension (EH), independently of blood pressure. Among renal disorders, albuminuria is more prevalent in patients with PA than EH, while GFR tends to be higher in PA due to glomerular hyperfiltration. Surgical and medical treatments for PA correct these effects of excess aldosterone, which sometimes uncover preexisting chronic kidney disease (CKD). Here we present a case of PA with CKD who manifested decline of glomerular filtration rate (GFR) and overt renal failure following resection of aldosterone-producing adenoma. Case report: A 53-year-old woman was diagnosed with hypertension at the age of 40. Her primary care physician started treatment with a calcium channel blocker (CCB). At the age of 49, she was diagnosed with Sjogren's syndrome (SS). Blood tests revealed severe hypokalemia and eGFR of 50 mL/min/1.73m2, while 24-hr urine collection showed urinary protein of 0.5 g per day. SS was suspected to underlie her renal disease. A renal biopsy was performed, and suggested nephrosclerosis and IgA nephropathy. On the other hand, a 11mm-sized tumor in the left adrenal gland was discovered during the investigation of secondary hypertension. PA was confirmed based on active renin concentration (ARC) of 4.3 pg/mL, plasma aldosterone concentration (PAC) of 342 pg/mL, an aldosterone-to-renin ratio of 79.5 (> 40), and 24-hr urinary aldosterone levels of 15.9 μg per day under the adequate salt-loaded condition. Adrenal venous sampling yielded aldosterone hypersecretion from the left adrenal vein, which indicated aldosterone-producing adenoma. Laparoscopic partial left adrenalectomy was performed and fully normalized ARC, PAC, and urinary aldosterone levels, which indicated biochemical cure of PA. Consequently, blood pressure had been well controlled with a single CCB. However, while her preoperative serum creatine level ranged from 0.9 to 1.1 mg/dL and eGFR was around 40–50 mL/min/1.73m2, her postoperative serum creatine level increased to 1.4 to 1.9 mg/dL and eGFR decreased to 25 to 35 mL/min/1.73m2 on average. In contrast, urinary protein level improved to less than 0.1 g/day, suggesting that post-treatment increase in creatine level indicated unveiling CKD rather than deterioration of renal function. Conclusion: PA treatment may unmask CKD through improving glomerular hyperfiltration from aldosterone excess.

Summary1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high‐sodium (8% NaCl) diet and heminephrectomy on PAC were examined.2. Feeding of the high‐sodium diet for 12 weeks similarly decreased PAC in TG and wild‐type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high‐sodium diet, but had no effect on PAC in WT rats fed a high‐sodium diet.3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high‐sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not.4. Nephrin and podocin mRNA levels, as determined by real‐time quantitative reverse transcription–polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)‐1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO‐1 mRNA levels in TG rats.5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.

Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

This study was conducted to determine the effects of a tablet combining losartan/hydrochlorothiazide (L/HCTZ) in comparison with losartan alone in Japanese diabetic patients with hypertension. Thirty consecutive Japanese diabetic patients with hypertension were randomly assigned to group A, receiving losartan alone for the first 3 months, then L/HCTZ for the next 3 months, or group B, receiving L/HCTZ for the first 3 months, then losartan alone for the next 3 months. Clinical and biological parameters were obtained before, and 3 and 6 months after the start of this study. The decreases in systolic and diastolic blood pressure (BP) during treatment with L/HCTZ were significantly greater than in treatment with losartan alone. Both treatments significantly and similarly decreased urinary albumin excretion, the cardio-ankle vascular index (CAVI) and augmentation index (AI). There was no significant difference in metabolic change during both the mono- and combination pharmacotherapies. The tablet combining L/HCTZ significantly reduced systolic and diastolic BP compared with the losartan monotherapy, and offered benefits similar to losartan monotherapy for albuminuria, arterial stiffness assessed by the CAVI and AI, and metabolic effects. Thus, the L/HCTZ tablet could be a useful drug for Japanese diabetic patients with hypertension.

The (pro)renin receptor ((P)RR) is known to play an important role in the pathogenesis of vascular complications in diabetes mellitus and hypertension through its function in activating the local renin-angiotensin system. Recent studies have shown that the (P)RR is an accessory protein of the vacuolar H(+)-ATPase, suggesting a more fundamental and developmental function. In this study, smooth muscle cell-specific (P)RR/Atp6ap2 conditional knockout mice were generated. Smooth muscle cell-specific ablation of the (P)RR resulted in nonatherogenic sclerosis in the abdominal aorta. The deletion of the (P)RR did not affect ambulatory blood pressure levels. In cultured murine vascular smooth muscle cells (VSMCs), ablation of the (P)RR suppressed the expression of the Vo subunit c of the vacuolar H(+)-ATPase and impaired the cell recycling system, leading to autophagic cell death. In addition, loss of the (P)RR in VSMCs induced the expression of monocyte chemotactic protein-1 and interleukin-6 mRNAs. These results suggest that the (P)RR is essential for cell survival and downregulation of vascular inflammation in murine VSMCs through maintaining normal function of the vacuolar H(+)-ATPase.