Novel trial for the treatment of steroid dependency in minimal change disease: combined therapy of camostat mesilate and glycyrrhizin.
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Adolescent↗
Biomedical subjects
Sadayoshi Ito
Publications and source records attributed to Sadayoshi Ito.
Detection of mRNA for alpha-3 chain of type IV collagen in the glomerular epithelium, and the effect of perfused elastase on its expression.
BACKGROUND: The type IV collagen is a complex of trimetric molecule composed of six genetically distinct polypeptide chains; alpha1-6(IV). Since alpha3(IV) distribute specifically in the glomerular basement membrane (GBM) of glomerular capillary, we tried to develop the detection methods for the transcripts of alpha3(IV) in glomerular epithelial cells (GEC) which produce most of the components for GBM. Then, using these molecular techniques, the influence of elastase, one of the proteases released from activated polymorphonuclear leukocytes at the site of inflammation, on GEC was determined as manifested by expressional alteration of alpha3(IV) mRNA. METHODS: DIG-labeled oligo-DNA probe designating non-collagenous region of alpha3(IV) was used for in situ hybridization. Semiquantitative measurement of alpha3(IV) in the renal cortex was performed by PCR reactions, each reaction being normalized by that for GAPDH. Then, the femoral artery of each of 18 Sprague-Dawley rats was catheterized and the left kidney was perfused with saline alone (0.5 ml) or saline containing 100 microg/ml elastase. After collection of urine for 24 h, the left kidney was harvested for analysis of mRNA (4 for in situ hybridization and 5 kidneys for PCR analysis). RESULTS: Antisense cDNA probe and PCR reaction well identified alpha3(IV) mRNA in the cytoplasm of GEC and in the renal cortex, respectively. Urinary protein excreted by rats with elastase perfusion was 47.2 +/- 3.8 mg/24 h but this was only 13.9 +/- 1.1 mg/24 h in control rats (mean +/- SEM, p < 0.05). In situ hybridization demonstrated that expression of alpha3(IV) mRNA in GEC was focally or diffusely reduced in the glomeruli of rats with elastase perfusion, whereas the transcripts were well stained in GEC of controls. PCR analysis showed about 25% decrease in transcripts of alpha3(IV) in the renal cortex of rats with elastase perfusion compared to those of control rats. CONCLUSIONS: alpha3(IV) mRNA was identified specifically in the GEC in the glomeruli. Co-incidence of proteinuria and reduced alpha3(IV) expression by elastase suggests adverse effects of elastase on GEC and close association between proteinuria and GEC injury.
Animals↗
Prevention of lymphocytic thyroiditis in iodide-treated non-obese diabetic mice lacking interferon regulatory factor-1.
OBJECTIVE: Interferon regulatory factor-1 (IRF-1) is a critical regulator of interferon-gamma(IFNgamma)-mediated immune responses. To determine whether IRF-1 is involved in the pathogenesis of thyroiditis in animal models, we evaluated the incidence of iodide-induced lymphocytic thyroiditis (LT) in non-obese diabetic (NOD) mice lacking IRF-1 as well as IRF-1 +/+ and +/- mice. DESIGN: IRF-1 +/+, +/- and -/- NOD mice at 6 weeks of age were fed water (group 1) or iodide water (group 2) for 8 weeks. METHODS: Thyroids were examined histopathologically and intrathyroidal lymphocytic infiltration was arbitrarily graded. Serum thyroxine (T(4)) and anti-mouse thyroglobulin antibody (anti-mTgAb) levels were measured. Spleen cell population was analyzed by flow cytometry, and IFNgamma and interleukin-10 produced by splenocytes were measured by enzyme-linked immunosorbent assay. RESULTS: In group 1, only 4.3% of NOD mice developed LT. In contrast, 67.6% of mice in group 2 developed the disease. Iodide treatment induced LT in more than 80% of IRF-1 +/+ and +/- mice. However, no IRF-1 -/- mice in group 2 developed LT. There was no difference in both serum anti-mTgAb and T(4) levels among the three IRF-1 genotypes of NOD mice. Numbers of splenic CD8(+) T cells and IFNgamma production by Concanavalin A-stimulated splenocytes were markedly decreased in IRF-1-deficient NOD mice. CONCLUSIONS: IRF-1 is involved in the development of iodide-induced LT in NOD mice.
Animals↗
Biphasic vasodilator action of troglitazone on the renal microcirculation.
Recent studies have demonstrated that thiazolidinediones, novel antidiabetic compounds that improve the insulin sensitivity, lower BP and decrease urinary protein excretion. However, neither the target vasculature nor the underlying mechanism for their actions is well understood. In this study, the action of troglitazone (Tro), a thiazolidinedione compound, on the glomerular afferent (Af-Arts) and efferent (Ef-Arts) arterioles, crucial vascular segments to the control of glomerular hemodynamics, were directly examined. Rabbit Af-Arts or Ef-Arts were microdissected from the superficial cortex and perfused at constant pressure. Increasing doses of Tro (10(-8) to 10(-5) M) were added to both the bath and lumen of preconstricted arterioles. In Af-Arts, Tro caused dose-dependent and biphasic dilation. Tro at 10(-5) M increased the diameter by 28 +/- 6% (n = 8, P < 0.01) until 20 min, with the diameter remaining at this level for 60 min, and then Tro began to dilate Af-Arts again. At 120 min, Tro at 10(-5) M further increased the diameter by 23 +/- 4% (n = 6). Disrupting the endothelium had no effect on either dilation (n = 7 or n = 5). Pretreatment with SKF 96365 (50 microM), which inhibits both voltage- and receptor-operated calcium channels, abolished the early-phase dilation without affecting the late-phase dilation; 20 or 120 min after adding Tro at 10(-5) M, the diameter increased by 4 +/- 2% (n = 7) or 28 +/- 3% (n = 6), respectively. In contrast to Af-Arts, Tro caused monophasic dilation in Ef-Arts; Tro at 10(-5) M did not cause significant dilation until 80 min, and at 120 min the diameter increased by 37 +/- 4% (n = 5). These results suggest that in the Af-Art Tro has biphasic endothelium-independent vasodilator action, which is partly mediated by an inhibition of calcium influx. This vasodilator action may play a role in the BP-lowering effect of Tro. In addition, by dilating the postglomerular Ef-Art, Tro may decrease the glomerular capillary pressure and hence the excretion of urinary protein.
Angiotensin II↗
Posttranscriptional compensation for heterozygous disruption of the kidney-specific NaK2Cl cotransporter gene.
Mice homozygous for a loss of function mutation of the kidney-specific NaK2Cl cotransporter, BSC1/NKCC2, do not survive. Here the effects of loss of one copy of the gene are studied. NKCC2 mRNA of NKCC2 +/- kidney was 55 +/- 6% of +/+, yet no differences were found between NKCC2 +/+ and +/- mice in BP, blood gas, electrolytes, creatinine, plasma renin concentration, urine volume and osmolality, ability to concentrate and dilute urine, and response to furosemide. When mice were challenged with 180 mM NH(4)Cl, plasma ammonia and urinary ammonia excretion were increased twofold and fivefold, respectively, but there was still no difference between the two genotypes. NKCC2 +/- mice had a near-normal level of NKCC2 protein and no clear change in the distribution of NKCC2 in the thick ascending limb (TAL) cells. In vitro microperfusion of isolated TAL showed no significant difference between the two genotypes in the basal and vasopressin-stimulated capacity to reabsorb NaCl. There was no difference in the mRNA expressions of thiazide-sensitive NaCl cotransporter, epithelial Na channel (ENaC), aquaporin-2, ROMK, and NaKATPase. Halving the mRNA expression of NKCC2 does not affect BP or fluid balance because of compensatory factors that restore the protein level to near normal. One possible factor is a regulated increase in the movement of cytoplasmic protein to the luminal membrane leading to a restoration of functional transporter to an essentially wild type level.
Adaptation, Physiological↗
Involvement of GTP-binding protein in pancreatic cAMP-mediated exocytosis.
We studied cAMP-mediated exocytosis in rat pancreatic acinar cells. We monitored changes in the membrane capacitance (DeltaC), which reflects the granule fusion/retrieval process, with whole-cell patch-clamp capacitance measurement. The rise in cellular cAMP, caused indirectly by receptor activation by vasoactive intestinal polypeptide or directly by dibutyryl cyclic AMP, was able to induce an increase in DeltaC independently of cellular Ca2+. Using the latter stimulation, we estimated the magnitude of the response to internal GTPgammaS [guanosine 5'-(gamma-thio)trisphosphate] and/or GDPbetaS [guanosine 5'-(beta-thio)diphosphate]. The internal GTPgammaS and GDPbetaS amplified and depressed the response, respectively. Thus, the cellular cAMP alone can trigger granule insertion independently of cellular Ca2+ and it can be controlled by cellular GTP-binding proteins, presumably those belonging to the Rab family.
Acetylcholine↗
High prevalence and adverse effect of hepatitis C virus infection in type II diabetic-related nephropathy.
Over a 4-yr period in the northeast region of Japan (Tohoku), 3643 patients for whom a renal biopsy was available were screened. In addition, 2370 biopsied patients for whom hepatitis C virus (HCV) serology was available were evaluated. The prevalence of HCV infection was investigated in the 2370 biopsied patients. The highest prevalence of HCV infection was found in type II diabetic-related glomerulosclerosis (II-DGS) (24 of 123; 19.5%). At renal biopsy, clinical and laboratory findings and histologic parameters were comparable between the HCV-positive and -negative II-DGS groups. After renal biopsy, the decline of renal function reflected by the slope of reciprocal serum creatinine (1/S(Cr)) was significantly greater in the HCV-positive group than in the HCV-negative group (P = 0.001). The log-rank test performed on the renal survival curves showed a significant difference in the two groups (P = 0.019). According to a multiple linear regression analysis adjusted for the effect of age, gender, BP, HbA1c, urinary protein excretion, and histologic parameters as covariates, urinary protein excretion (P = 0.011), severe arteriolar hyalinosis (P = 0.006), and HCV infection (P < 0.001) were significantly associated with 1/S(Cr) slope. Finally, HCV infection was randomly examined in 545 outpatients and inpatients with type II diabetes mellitus who did not undergo renal biopsy. Of these, 56 patients were positive for HCV antibody (10.3%), and their proteinuria was heavier than in 489 HCV-negative patients (P = 0.001). This study reveals that HCV infection is present at a high rate in type II diabetic-related nephropathy and may have an adverse effect on the progression of the disease.
Aged↗
Spironolactone further reduces urinary albumin excretion and plasma B-type natriuretic peptide levels in hypertensive type II diabetes treated with angiotensin-converting enzyme inhibitor.
1. Over the course of treatment with angiotensin-converting enzyme inhibitor (ACEI), plasma levels of aldosterone have been shown to increase and this increase would blunt the effectiveness of the ACEI (aldosterone escape phenomenon). 2. In the present study, we assessed a potential renal benefit of additional aldosterone blockade with spironolactone in hypertensive diabetic patients treated with ACEI showing the phase of aldosterone escape. 3. The present clinical study was a randomized prospective study to assess difference between the clinical effects of spironolactone and furosemide. Thirty hypertensive type II diabetics (DM2) with a urinary alubumin:creatinine ratio (ACR) above 30 mg/g creatinine (showing albuminuria) and plasma B-type natriuretic peptide (BNP) levels above 100 pg/mL (showing mild heart failure) were treated with an ACEI (imidapril 5 mg/day) for 1 year and then randomly divided into two groups, one group receiving additional spironolactone (25 mg/day) treatment and the other receiving furosemide (20 mg/day) treatment. Blood pressure, ACR and plasma BNP levels were monitored in both groups. 4. Treatment with the ACEI reduced ACR initially but, in 1 year, ACR tended to increase. Additional spironolactone treatment progressively reduced ACR, whereas furosemide treatment did not show any effect. Plasma BNP levels were reduced by ACEI and were further reduced by additional spironolactone treatment, but not furosemide treatment. Blood pressure levels in both groups were comparable. 5. In conclusion, additional therapy with spironolactone in ACEI treatment exerts a renoprotective, as well as cardioprotective, effect in hypertensive diabetes.
Albuminuria↗
Aldosterone-producing adenoma accompanied with renal artery stenosis.
We describe a case of secondary hypertension in which aldosterone-producing adenoma (APA) and renal artery stenosis (RAS) coexisted. RAS caused a significant pressure gradient, and successful angioplasty of it improved the affected renal function but did not reduce the systemic blood pressure (SBP). Surgical resection of APA performed several months later reduced SBP. In cases of suspected secondary hypertension, other cause(s) of hypertension should be considered, if hypertension persists after correction of one possible cause.
Adenoma↗