. Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol 283: L346-L353, 2002. First published March 29, 2002 10.1152/ajplung.00385.2001.-During hepatopulmonary syndrome caused by liver cirrhosis, pulmonary endothelial nitric oxide (NO) synthase (NOS) expression and NO production are increased. Increased NO contributes to the blunted hypoxic pressor response (HPR) during cirrhosis and may induce heme oxygenase-1 (HO-1) expression and carbon monoxide (CO) production, exacerbating the blunted HPR. We hypothesized that NO regulates the expression of HO-1 during cirrhosis, contributing to hepatopulmonary syndrome. Cirrhosis was induced in rats by common bile duct ligation (CBDL). Rats were studied 2 and 5 wk after CBDL or sham surgery. Lung HO-1 expression was elevated 5 wk after CBDL. Liver HO-1 was increased at 2 wk and remained elevated at 5 wk. In catheterized rats, the blunted HPR was partially restored by HO inhibition. Rats treated with the NOS inhibitor N G -nitro-L-arginine methyl ester for the entire 2-or 5-wk duration had normalized HO-1 expression and HPR. These data provide in vivo evidence for the NO-mediated upregulation of HO-1 expression and support the concept that hepatopulmonary syndrome is multifactorial, involving not only NO, but also HO-1 and CO. carbon monoxide; cirrhosis; endothelial nitric oxide synthase; pulmonary vasoreactivity; calcium-activated potassium channels ENDOTHELIUM-DERIVED NITRIC OXIDE (NO) produced by the enzymatic activity of endothelial nitric oxide synthase (eNOS) has well-characterized actions as a vasodilator (33). Once produced, NO is freely diffusible and enters vascular smooth muscle cells (VSMCs) to activate soluble guanylate cyclase and produce guanosine 3Ј,5Ј-cyclic monophosphate (cGMP) (26,33). In pulmonary artery (PA) VSMCs, increased cGMP activates a cGMPsensitive kinase, which phosphorylates a calciumdependent potassium (K Ca ) channel leading to hyperpolarization and vasodilation (7,26,33). Although most of the NO production in the vascular endothelium is due to eNOS, some studies suggest that the two other isoforms of NOS, inducible NOS and neuronal NOS, may also be present in the vasculature and contribute to NO production (20,29,30).Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in the oxidative degradation of heme to biliverdin, releasing equimolar amounts of carbon monoxide (CO) and iron (5). Biliverdin is subsequently reduced to bilirubin by biliverdin reductase (5). CO, a gaseous messenger similar to NO, shares many properties with NO, including activation of guanylate cyclase, signal transduction, and gene regulation and may mediate important cellular functions (34).In addition to its action as a vasodilator, NO can regulate the expression of a variety of genes. In particular, there is solid evidence that NO regulates the expression of HO-1 (1, 4, 15). For example, treating aortic smooth muscle cells with the NO donor spermine NONOate (SNN) increases HO-1 gene transcription, resul...

Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme, catalyzing the oxidative cleavage of heme molecules to biliverdin, carbon monoxide, and iron. The present study was designed to investigate the role of HO-1 in the pathogenesis of renal dysfunction during cirrhosis. Biliary cirrhosis was induced in rats by common bile duct ligation (CBDL). Animals were studied 2 and 5 wk after surgery. In kidney from CBDL rats, HO-1 protein expression increased slightly at 2 wk but was abolished at 5 wk. In addition, we confirmed histologically that HO-1 expression was suppressed in renal tubules and interlobular arterioles in 5-wk-old CBDL rats. Conversely, HO-1 expression in liver was strongly increased. Consistent with the development of cirrhosis and renal dysfunction mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal blood flow (RBF) were decreased in CBDL rats compared with sham-operated controls. In sham rats, treatment with the selective HO inhibitor zinc protoporphyrin markedly decreased GFR and RBF to values similar to those measured in CBDL rats without decreasing MAP. In conclusion, decreased renal HO-1 expression contributes to deteriorated renal function and hemodynamics during cirrhosis. This finding provides a novel mechanism for the pathophysiology of renal dysfunction during cirrhosis.

Aim: Non-insulin-dependent diabetic mellitus model rats, Otsuka-Long-Evans-Tokushima-Fatty (OLETF), develop diabetic nephropathy presenting with mesangial expansion leading to glomerular sclerosis and thickening of the glomerular basement membrane (GBM), especially in elderly males. The effects of sex hormones and castration on the incidence of diabetes mellitus (DM) have been studied in this strain rat. However, there have been no detailed studies on the effects of castration and sex hormone in the development of diabetic nephropa-thy. Methods: In this study we examine the effect of cas-tration or estrogen on the development of glomerular injury in OLETF rats. Thirty male OLETF rats and 10 male long-Evans Tokushima Otsuka (LETO) rats as a normal control were used. OLETF rats were divided into three groups: group 1 received sham-operation, group 2 was castrated at 6 weeks, and group 3 was administered 0.1 mg estrogen subcutaneously once a month from 6 weeks to 58 weeks of age and LETO rats were assigned to group 4. Body weight, urinary protein and fasting blood glucose, serum albumin and other serum constituents were investigated every 12 weeks from 12 weeks to 60 weeks of age. In groups 1-3, glucose tolerance test was performed at 38 weeks. Each group was studied morphologically at the end of the experiment (60 weeks of age). Results: Castration attenuated proteinuria and glomerular sclerosis accompanied by an amelioration of glucose tolerance, a decrease in mesangial expansion and an attenuation of the GBM thickening. In contrast, although estrogen equally ameliorated glucose tolerance and attenuated the mesangial expansion and the GBM thickening, estrogen failed to attenuate proteinuria and glomerulosclerosis. A significant increase in glomer-ular tuft volume, and serum levels of growth hormone, total cholesterol and triglycerides was observed in the estrogen-treated rats as compared with the castrated rats. Conclusion: Besides the mechanisms involved in the development of diabetic nephropathy, other mechanisms may be involved and contribute to the development of glomerulosclerosis in the estrogen-treated rats, leading to a difference in glomerular injury between the castrated and estrogen-treated OLETF rats.

Hypercholesterolemic Imai rats spontaneously develop proteinuria and glomerulosclerosis, especially in males. Estrogen administration attenuated glomerular injury in male Imai rats, and the aggravating effect of ovariectomy in female rats is found. To clarify whether this aggravating effect of ovariectomy is due to a lack of estrogen, we administered estrogen to ovariectomized female Imai rats. At 6 weeks of age, group 1 (control) was sham-operated and group 2 was ovariectomized. Groups 3 and 4 were ovariectomized and received estrogen replacement therapy (0.1 mg in group 3 and 0.2 mg in group 4 once a month subcutaneously). Body weight, urinary protein and serum constituents were investigated every month from 3 to 6 months of age. At 6 months of age, rats were studied morphologically. Estrogen replacement therapy increased serum estrogen to levels close to those of controls when 0.1 mg was used, or higher when 0.2 mg was used. Estrogen replacement therapy with 0.1 mg did not eliminate the aggravating effect of ovariectomy on glomerular injury and rather aggravated it, but conversely therapy with 0.2 mg attenuated glomerular injury and abolished the aggravating effect of ovariectomy. Estrogen replacement therapy markedly elevated serum GH levels dose-dependently. These results suggested that other hormones as well as estrogen may play a protective role of the ovary for the development of glomerular injury, and that estrogen seems to exert a dual effect on glomerular injury.

Patient: Female, 44Final Diagnosis: Tubulointerstitial nephritis • uveitis syndromeSymptoms: —Medication: Loxoprofen sodium hydrateClinical Procedure: Renal biopsySpecialty: NephrologyObjective:Rare diseaseBackground:Although TINU syndrome is characterized by idiopathic TIN with bilateral anterior uveitis, few reports have provided a comprehensive summary of the features of this disorder. Previous reports have suggested that many Japanese patients had HLA-A2 and -A24 (7), but there is no evidence.Case Report:A 44-year-old female was referred to our hospital due to renal dysfunction in March 2012. After admission, her symptoms improved spontaneously without medication within 2 weeks. In the outpatient clinic, she was diagnosed with idiopathic bilateral anterior uveitis in May, and her renal dysfunction relapsed in November. A renal biopsy showed diffuse TIN. We made a diagnosis of TINU syndrome because we could not explain the origin, and treated her with a systemic corticosteroid. Her renal function and ocular symptoms have been improving. The patient had HLA-A24, -B7, -DR1, -C*07: 02 and -DQB1*05: 01: 01. We collected 102 Japanese cases in PubMed, Ovid MEDLINE, and the Japanese Medical Abstracts Society and compared our case with the previous cases.Conclusions:This disorder affects primarily young females (median age, 14 years), and the most common symptom is fever (44/102 cases). We conducted a statistical analysis using contingency table and Pearson’s chi-square test, for HLA-A2 and A24, and calculated the odds ratio (OR). There are no significant differences (A2 was present in 7/22 cases and in 19/50 controls, p value (P) 0.61, OR 0.76 (95% confidence interval (CI)) 0.27–2.2; A24 was present in 10/22 cases and in 33/50 controls, P 0.10, OR 0.43, CI 0.16–1.2).

Serum fT4 level was markedly lower without a change in fT3/fT4 ratio in ESRD. This may suggest typical carbohydrate-sufficient non-thyroidal illness. The specific reference values for ESRD were useful to evaluate borderline thyroid dysfunction and to evaluate the prevalence of the patients with primary thyroid dysfunction in ESRD.

Case 1: A 59-year-old Japanese woman with rheumatoid arthritis (RA) for 36 years was admitted for evaluation of deteriorating renal function. Her serum creatine was 4.2 mg/dL, and proteinuria was 6.5 g daily. Renal and duodenal biopsy revealed AA amyloidosis. After treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), proteinuria decreased to 1.1 g daily. The patient’s renal function subsequently remained stable for 8 years. Case 2: A 71-year-old Japanese man with RA for 30 years was admitted due to deterioration of renal function. Serum creatine was 2.9 mg/dL, and urinary protein excretion was 0.06 g daily. Renal and duodenal biopsy identified AA amyloidosis. Tocilizumab was initiated, and his renal function remained stable for 6 years. The 2 nd duodenal biopsy showed a marked decrease of AA amyloid deposits. Conclusion: These two cases suggest that tocilizumab may preserve renal function in the setting of end-stage kidney disease and shift the point of no return for RA patients with AA amyloidosis and renal dysfunction.

BackgroundConcerns about sodium overload when using sodium polystyrene sulfonate (Na-resin) as an ion-exchange resin for the treatment of hyperkalemia led our institution to gradually shift to the use of calcium polystyrene sulfonate (Ca-resin). However, as serum potassium levels were insufficiently controlled and patients experienced constipation, we returned to using Na-resin and observed better results than previously.ObjectiveAs few papers have examined the potassium adsorption ability of Ca-resin compared with Na-resin, we investigated this issue within our institution.MethodsWe studied potassium adsorption in patients who switched from Ca-resin to an equivalent amount of Na-resin (change group). We also investigated the incidence of sodium loading with Na-resin, including in patients newly commencing Na-resin treatment (new start group).ResultsMean (± standard deviation) serum potassium levels decreased significantly, from 5.5 ± 0.6 to 4.9 ± 0.6 mEq/l in the change group and from 5.9 ± 0.4 to 4.7 ± 0.6 mEq/l in the new start group. No changes were observed in blood pressure, weight gain or serum sodium levels in the change group, but serum sodium levels in the new start group increased significantly, from 137.4 ± 2.3 to 139.0 ± 2.5 mEq/l, although they remained within the normal range.ConclusionsOur results indicate that Na-resin exhibited an advantage in treating hyperkalemia when used in small amounts. However, when prescribing an ion-exchange resin at a higher dose, physicians should select the type and amount of resin according to the sodium and/or calcium load in each case.