Klotho is a circulating protein, and Klotho deficiency disturbs endothelial integrity, but the molecular mechanism is not fully clarified. We report that vascular endothelium in Klotho-deficient mice showed hyperpermeability with increased apoptosis and down-regulation of vascular endothelial (VE)-cadherin because of an increase in VEGF-mediated internal calcium concentration ([Ca 2+ ]i) influx and hyperactivation of Ca 2+ -dependent proteases. Immunohistochemical analysis, the pull-down assay using Klotho-fixed agarose, and FRET confocal imaging confirmed that Klotho protein binds directly to VEGF receptor 2 (VEGFR-2) and endothelial, transient-receptor potential canonical Ca 2+ channel 1 (TRPC-1) and strengthens the association to promote their cointernalization. An in vitro mutagenesis study revealed that the second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of VEGFR-2 and the third extracellular loop of TRPC-1. In Klotho-deficient endothelial cells, VEGF-mediated internalization of the VEGFR-2/TRPC-1 complex was impaired, and surface TRPC-1 expression increased 2.2-fold; these effects were reversed by supplementation of Klotho protein. VEGF-mediated elevation of [Ca 2+ ]i was sustained at higher levels in an extracellular Ca 2+ -dependent manner, and normalization of TRCP-1 expression restored the abnormal [Ca 2+ ]i handling. These findings provide evidence that Klotho protein is associated with VEGFR-2/TRPC-1 in causing cointernalization, thus regulating TRPC-1–mediated Ca 2+ entry to maintain endothelial integrity.

Peritonitis due to nontuberculous mycobacterium in peritoneal dialysis (PD) patients is rare. However, when it occurs, PD catheter removal is required in most cases because of resistance to antibiotic therapy. We report a case of Mycobacterium abscessus peritonitis subsequent to tunnel infection after PD catheter-replacement surgery. The patient underwent this surgery as her tunnel infection had not resolved following the usual 3 month course of antibiotic therapy. After surgery, tunnel infection of the second catheter and peritonitis occurred. Nontuberculous mycobacteria were detected on acid-fast stain from both the old and new exit-site drainage and the peritoneal effluent. The mycobacteria were identified as M. abscessus. Removal of the new catheter and surgical excision of the previous catheter tunnel were performed and multiple antibiotics were started. After 3 months the postsurgical wounds had healed completely. This case demonstrates the importance of further evaluation of unidentified PD catheter-related infections, including an examination for nontuberculous mycobacterium.

OBJECTIVE: This open-label, randomized controlled trial investigated the effects of cilnidipine, an L/N-type calcium channel blocker (CCB), in patients with chronic kidney disease (CKD). METHODS: Sixty patients with CKD and well-controlled hypertension being treated with a reninangiotensin system (RAS) inhibitor and an L-type CCB (L-CCB) were randomly assigned either to switch from the L-CCB to cilnidipine after a 4-week observation period or to continue with L-CCB treatment. Blood pressure, heart rate and renal function were monitored for 12 months. Data were available for analysis from 50 patients: 24 from the cilnidipine group and 26 from the L-CCB group. RESULTS: Blood pressure was well controlled in both groups. After 12 months, proteinuria and heart rate were significantly decreased in the cilnidipine group, but proteinuria increased and heart rate remained unchanged in the L-CCB group. There was a significant positive correlation between the percentage changes in proteinuria and heart rate. CONCLUSIONS: Cilnidipine has antihypertensive effects equivalent to those of L-CCBs. In patients with CKD, proteinuria can be decreased by switching from an L-CCB to cilnidipine, thereby improving renal function.

7Recently, the authors experienced four patients who had refractory hypertension and neurovascular compression of the rostral ventrolateral medulla (RVLM). One of them, a 49-year-old woman, had undergone continuous intravenous drip injections of calcium channel blockers and b-blockers for more than 3 years because of severe and refractory hypertension. The patients had undergone microvascular decompression (MVD) of the RVLM, and the changes in blood pressure (BP) and sympathetic nerve activities were recorded. In these patients, BP decreased to the normal range without any antihypertensive drugs 2 to 3 months after MVD. The tibial sympathetic nerve activities under resting and stress conditions significantly decreased, and plasma levels of norepinephrine, urinary levels of adrenaline, and plasma renin activity were also significantly decreased after MVD of RVLM. In some patients with refractory hypertension, arterial compression of the RVLM enhances sympathetic nerve activity and renin-angiotensin system to thereby increase BP. In these patients, the operative decompression of the RVLM could lower BP via restoration of sympathetic nerve activities and the renin-angiotensin system. J Clin Hypertens (Greenwich). 2011;13:818-820. Ó2011 Wiley Periodicals, Inc.Sympathetic hyperactivity of central origin is implicated in the pathogenesis of hypertension. However, the precise mechanisms that cause central sympathetic hyperactivity remain unclear. The rostral ventrolateral medulla (RVLM) contains neurons that are the major tonic source of supraspinal sympathoexcitatory outflow to the heart, kidneys, and vessels.1 In humans, RVLM exists near the dorsal root entry zone of cranial nerves IX and X. A possible association between essential hypertension and neurovascular compression (NVC) of the RVLM has been reported by autopsy, 2 magnetic resonance imaging ⁄ magnetic resonance angiography (MRI ⁄ MRA), 3 and intraoperative observation.4 Some of these reports referred to enhanced sympathetic activities in hypertensive patients with NVC compared with hypertensive patients without NVC or normotensive patients. In rats, we reported that pulsatile compression of the RVLM leads to activation of RVLM neurons to elicit sympathetic hyperactivity and blood pressure (BP) elevation. 5 A causative relationship between NVC of the RVLM and hypertension was further ascertained by the fact that surgical microvascular decompression (MVD) substantially decreased BP in patients with refractory hypertension. 4 However, except in our case report, there has been no report that neurovascular decompression of the RVLM restores sympathetic activity to thereby decrease BP. 6 Therefore, in the present report, the effects of surgical MVD of the RVLM on BP, sympathetic nerve activities, and reninangiotensin system were explored in patients with refractory hypertension. METHODS PatientsFour patients were referred to our hospital because of refractory hypertension. Of these, 3 were women and 1 was a man, ranging in age between 35 and 51 years. Three of the...

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