Hiroko Ito

Human renal mesangial cells produce aldosterone in response to low-density lipoprotein (LDL)

Systemic aldosterone plays an important role in the development of the microvascular disease and glomerular damage of the kidney in patients with diabetes mellitus and hyperlipidemia. Here, we investigated the possibility of local production of aldosterone in the kidney, using human primary glomerular mesangial cells. These cells produced both pregnenolone and aldosterone measured by specific radioimmunoassay and/or gas chromatography/mass spectrometry (GC/MS) methods. The production of both steroids was significantly stimulated by treatment with LDL, while angiotensin II had a synergistic effect. Adrenocorticotropic hormone (ACTH) and (Bu)2cAMP, on the other hand, failed to stimulate aldosterone production by these cells, suggesting that the local production of this steroid by mesangial cells is regulated differently from that of adrenal zona glomerulosa cells. Mesangial cells expressed the mRNA of the LDL receptor and steroidogenic enzymes, such as P450scc, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 21-hydroxylase and CYP11B2. Mesangial cells also expressed mRNA of the mineralocorticoid receptor (MR), and LDL stimulated its abundance by three-fold, while spironolactone, a completive antagonist of aldosterone, completely abolished this LDL effect. Since MR is a known mineralocorticoid-responsive gene as well as an intracellular receptor molecule for this steroid, these results suggest that locally produced aldosterone is biologically active, stimulating the transcription rates of the mineralocorticoid-responsive genes by activating the MR in mesangial cells. These pieces of evidence indicate that human mesangial cells are an aldosterone-producing tissue in which LDL plays a major regulatory role. Therefore, human renal mesangial endocrine system may contribute to local aldosterone concentrations and effects in the renal glomerulus independently of the systemic renin--angiotensin--aldosterone system and may participate in the development and progression of glomerular damage in several pathologic conditions.

A Capture-Safe Test Generation Scheme for At-Speed Scan Testing

Capture-safety, defined as the avoidance of any timing error due to unduly high launch switching activity in capture mode during at-speed scan testing, is critical for avoiding test- induced yield loss. Although point techniques are available for reducing capture IR-drop, there is a lack of complete capture-safe test generation flows. The paper addresses this problem by proposing a novel and practical capture-safe test generation scheme, featuring (1) reliable capture-safety checking and (2) effective capture-safety improvement by combining X-bit identification & X-filling with low launch- switching-activity test generation. This scheme is compatible with existing ATPG flows, and achieves capture-safety with no changes in the circuit-under-test or the clocking scheme.

Effect of ACE gene on diabetic nephropathy in NIDDM patients with insulin resistance

We investigated the influence of the angiotensin-converting enzyme (ACE) gene on the onset and/or progression of diabetic nephropathy in 62 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM; type II diabetes). Because a number of factors are believed to be involved in the onset and/or progression of diabetic nephropathy, especially in patients with NIDDM, we selected the patients with well-matched risk factors, duration of disease, glycemic control, blood pressure, and others. All patients had normal renal function and none were receiving ACE inhibitors. Patients were divided into three groups according to albumin excretion rate (AER): group A, patients with an AER less than 15 microg/min (n = 29); group B, patients with an AER between 15 and 70 microg/min (n = 19); and group C, patients with an AER greater than 70 microg/min (n = 14). The glucose disposal rate was estimated using a euglycemic hyperinsulinemic clamp. We determined the mean glucose disposal rate in 132 patients with NIDDM (6.49 mg/kg/min). Patients with a glucose disposal rate less than the mean rate were considered to have a high degree of insulin resistance (n = 36). The presence of an insertion/deletion (I/D) polymorphism of the ACE gene was determined by the polymerase chain reaction method. Among patients with a high degree of insulin resistance, diabetic nephropathy was present in 2 of 11 patients with the II genotype of the ACE gene compared with 19 of 25 patients with the ID or DD genotype (P = 0.0024). The prevalence of diabetic nephropathy was greater in patients with both significant insulin resistance and the D allele (19 of 25) than in the remaining patients (14 of 37; odds ratio, 5.20). These results suggest that the ACE gene influences the onset and/or progression of diabetic nephropathy in patients with NIDDM with significant insulin resistance.

The Alkalizer Citrate Reduces Serum Uric Acid Levels and Improves Renal Function in Hyperuricemic Patients Treated with the Xanthine Oxidase Inhibitor Allopurinol

Objective. Hyperuricemia, an integral component of metabolic syndrome, is a major health problem causing gout and renal damage. Urine alkalizers such as citrate preparations facilitate renal excretion of the uric acid, but its supportive effect on xanthine oxidase inhibitors has not been tested yet. We performed a randomized, prospective study of the effect of a combination of allopurinol and a citrate preparation on renal function in patients with hyperuricemia, employing 70 patients who had hyperuricemia with serum uric acid levels ≥7.0 mg/dL, or those diagnosed as having hyperuricemia in the past. Methods. They were randomly enrolled into two study groups: the allopurinol monotherapy (MT) group or combination treatment (CT) group with allopurinol and a citrate preparation. Allopurinol (100–200 mg/day) in the absence or presence of a citrate preparation (3 g/day) was administered for 12 weeks and levels of serum uric acid, its urinary clearance (Cua), and the renal glomerular filtration rates assessed with the creatinine clearance (Ccr) were evaluated before and after the treatment. Results. Serum levels of uric acid decreased significantly in both groups, whereas the change observed was much greater in CT group. Cua was significantly increased in CT group but not in MT group. Ccr was not altered in both groups in general, whereas it was significantly increased in a fraction of CT group with decreased renal function. Conclusions. These results indicate that an additional use of citrate preparations with xanthine oxidase inhibitors is beneficial for patients with hyperuricemia, reducing circulating uric acid and improving their glomerular filtration rates.

Alkalizer Administration Improves Renal Function in Hyperuricemia Associated with Obesity

We evaluated the combination effect of the alkalizer citrate with the xanthine oxidase inhibitor allopurinol on renal function and uric acid in patients with hyperuricemia associated with obesity and/or metabolic syndrome (MetS), who were extracted from among the subjects enrolled in a prospective randomized controlled study aimed at assessing the efficacy of such a combination for improving renal function. We also conducted a post hoc analysis to examine influences on lipid profiles. Patients who consented to participate in the study were randomly allocated to receive either allopurinol alone (monotherapy) or in combination with a citrate preparation (combination therapy). The analysis population consisted of 31 obese patients with a body mass index greater than 25 kg/m2 (monotherapy, 15 patients; combination therapy, 16 patients). The creatinine clearance rate (Ccr), serum uric acid levels, and lipid profiles were measured before and at 12 weeks after the start of treatment. In the combination therapy group, Ccr increased significantly and serum uric acid levels decreased significantly in obese patients, while Ccr tended to increase and serum uric acid levels decreased, though not significantly, in patients with MetS-related clinical parameters. Overall, blood triglyceride levels tended to improve in the combination therapy group as compared with the monotherapy group.