Comparison of serum alkaline phosphatase levels between two measurement methods in chronic hemodialysis patients in Japan: involvement of ABO blood group system and relationship with mortality risk.

BACKGROUND: Elevated serum alkaline phosphatase (ALP) levels are a risk factor for all-cause mortality in hemodialysis patients. Traditionally in Japan, ALP measurements were conducted using the JSCC method, which yields higher ALP measurement values than the IFCC method, mainly due to its increased sensitivity to intestinal ALP. METHODS: Serum total ALP levels before and after switching the assay method from JSCC to IFCC were compared among different blood types in 521 hemodialysis patients (Study 1). The association between ALP levels measured by the JSCC method and 7-year mortality was analyzed, including blood types and liver function parameters as covariates, in 510 hemodialysis patients (Study 2). RESULTS: ALP levels measured by the JSCC method were approximately three times higher than those measured by the IFCC method, with significant elevation in patients with blood types B and O compared to those with blood types A and AB. Similarly, ALP levels measured by the IFCC method were significantly higher in patients with blood types B and O compared to those with blood types A and AB (Study 1). The highest tertile of ALP levels showed a significantly increased risk of all-cause mortality, even after adjusting for patient background. However, this significance disappeared when serum liver function-related or inflammatory markers were included as covariates (Study 2). CONCLUSION: ALP levels measured by the JSCC method are associated with life prognosis, but caution should be exercised due to their elevation in patients with blood types B and O and in those with hepatic dysfunction or inflammation.

Association between phosphate binder pill burden and mortality risk in patients on maintenance hemodialysis: a single-center cohort study with 7-year follow-up of 513 patients.

BACKGROUND: Dialysis patients often take multiple oral medications, leading to a high pill burden. Phosphate binders (PBs) account for a large proportion of this daily pill burden (DPB). The relationship between DPB and mortality risk remains unclear, and we hypothesized that this relationship might be influenced by the proportion of PBs to all medications. METHODS: We divided DPB into those derived from PBs and non-PB drugs and analyzed the association with mortality risk over a 7-year period in 513 chronic hemodialysis patients using a baseline model. RESULTS: The median (interquartile range) DPB from all drugs was 15.8 (11.2-21.0) pills/day/patient, and the median ratio of PB pills to all drug pills was 29.3 (13.7-45.9)% at baseline. During a median observation period of 5.2 years, 161 patients (31.4%) died. Kaplan-Meier analysis showed no significant difference in all-cause mortality between PB users and non-users. However, a significant survival advantage was observed in the highest tertile of DPB from PBs compared to the lowest tertile. Conversely, the highest tertile of DPB from non-PB drugs was associated with worse survival. Consequently, the highest tertile of the ratio of PBs to all pills was associated with better survival. This association remained significant even after adjusting for patient characteristics in the Cox proportional hazards model. However, when serum nutritional parameters were included as covariates, the significant association disappeared. CONCLUSIONS: Dialysis patients prescribed a higher rate of PB pills to all medications exhibited a lower mortality risk, possibly due to their better nutritional status.

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic properties. We recently reported that an SGLT2 inhibitor ameliorated extracellular fluid expansion with a transient increase in urinary Na+ excretion. However, the effects of SGLT2 inhibitors on fluid distribution in comparison to conventional diuretics remain unclear. METHODS: Forty chronic kidney disease patients with fluid retention (average estimated glomerular filtration rate 29.2 ± 3.2 mL/min per 1.73 m2 ) were divided into the SGLT2 inhibitor dapagliflozin (DAPA), loop diuretic furosemide (FR) and vasopressin V2 receptor antagonist tolvaptan (TLV). The body fluid volume was measured on days 0 and 7 using a bioimpedance analysis device. RESULTS: In all three groups, body weight was significantly and similarly decreased, and urine volume numerically increased for 7 days. Bioimpedance analysis showed that the changes in intracellular water were similar, but that there were significant changes in the extracellular water (ECW) (DAPA -8.4 ± 1.7, FR -12.5 ± 1.3, TLV -7.4 ± 1.5%, P = 0.048). As a result, the change in the ratio of ECW to total body water in the DAPA group was significantly smaller than that in the FR group, but numerically larger than that in the TLV group (DAPA -1.5 ± 0.5, FR -3.6 ± 0.5, TLV -0.5 ± 0.4%, P < 0.001). CONCLUSION: Sodium-glucose cotransporter 2 inhibitor DAPA predominantly decreased the ECW with a mild increase in urine volume, but the change in the ECW/total body water was smaller than that in patients treated with FR, and larger than that in patients treated with TLV, suggesting that the effects of SGLT2 inhibitors on fluid distribution may differ from those of conventional diuretics.

Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat.

The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 wk) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a nonobese type 2 diabetic model, and nondiabetic Sprague-Dawley rats. In nondiabetic rats, Ipra increased urinary excretion of Na+ (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these four parameters, but Ipra had no further effect, probably because of its antihyperglycemic effect, such that glucosuria and, as a consequence, food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the four groups. To study the impact of food and fluid intake, nondiabetic rats were treated for 7 days with Veh, Ipra, or Ipra+pair feeding+pair drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, whereas Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize BFV, including compensatory increases in fluid and food intake.

Physiological roles of claudins in kidney tubule paracellular transport.

The paracellular pathways in renal tubular epithelia such as the proximal tubules, which reabsorb the largest fraction of filtered solutes and water and are leaky epithelia, are important routes for transepithelial transport of solutes and water. Movement occurs passively via an extracellular route through the tight junction between cells. The characteristics of paracellular transport vary among different nephron segments with leaky or tighter epithelia. Claudins expressed at tight junctions form pores and barriers for paracellular transport. Claudins are from a multigene family, comprising at least 27 members in mammals. Multiple claudins are expressed at tight junctions of individual nephron segments in a nephron segment-specific manner. Over the last decade, there have been advances in our understanding of the structure and functions of claudins. This paper is a review of our current knowledge of claudins, with special emphasis on their physiological roles in proximal tubule paracellular solute and water transport.

The association between soluble intercellular adhesion molecule-1 levels in drained dialysate and peritoneal injury in peritoneal dialysis.

BACKGROUND: Chronic inflammation of the peritoneum causes peritoneal injury in patients on peritoneal dialysis. Intercellular adhesion molecule-1 and its circulating form, soluble intercellular adhesion molecule-1, play pivotal roles in inflammation. However, their role in peritoneal injury is unclear. METHODS: We measured changes in intercellular adhesion molecule-1 expression in the peritoneum of a peritoneal injury model in rats. The associations between soluble intercellular adhesion molecule-1 levels in drained dialysate and the solute transport rate (D/P-Cr and D/D0-glucose) determined by the peritoneal equilibration test, and matrix metalloproteinase-2 levels in drained dialysate were investigated in 94 peritoneal drained dialysate samples. RESULTS: Intercellular adhesion molecule-1 expression was increased in the peritoneum of rats with peritoneal injury. Soluble intercellular adhesion molecule-1 levels in drained dialysate were significantly positively correlated with D/P-Cr (r = .51, p < .01) and inversely correlated with D/D0-glucose (r = -.44, p < .01). They were also significantly positively correlated with matrix metalloproteinase-2 levels in drained dialysate (r = .86, p < .01). CONCLUSIONS: Intercellular adhesion molecule-1expression is increased in the peritoneum of a peritoneal injury model in the rat, and soluble intercellular adhesion molecule-1 levels in drained dialysate are associated with peritoneal injury in patients on peritoneal dialysis. These results suggest that soluble intercellular adhesion molecule-1 could be a novel biomarker of peritoneal injury in patients on peritoneal dialysis.

HIF-1α mediates Hypoxia-induced epithelial-mesenchymal transition in peritoneal mesothelial cells.

The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells plays a pivotal role in the development of peritoneal fibrosis. The pathological effects of hypoxia on mesothelial cell EMT have not been fully elucidated. In this study, we, therefore, investigated the effects of hypoxia on EMT in mesothelial cells. Human mesothelial (MeT-5A) cells and primary-cultured rat mesothelial cells were cultured under hypoxic conditions (1% O(2)) for up to 72 h. Changes in cell type were then determined by investigating changes in morphology and in expression of epithelial (E-cadherin and occludin) and mesenchymal (fibronectin-1, vimentin and α-smooth muscle actin) cell markers. In some cases, MeT-5A cells were cultured under hypoxic conditions with a HIF-1α inhibitor and then assessed for changes in morphology and for altered expression of signaling molecules, such as HIF-1α, Snail-1, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2). Levels of HIF-1α, Snail-1, VEGF, and MMP-2 in Met-5A cells were increased by hypoxia. Levels of epithelial cell markers were decreased and those of mesenchymal cell markers were increased. Cell morphology also changed from a cobblestone-like monolayer to spindle-shaped fibroblast-like cells in response to hypoxia. Inhibition of HIF-1α signaling by a HIF-1α inhibitor abrogated these changes. The cell marker and morphological changes induced by hypoxia were also observed in primary-cultured rat mesothelial cells. We can conclude that hypoxia induces EMT in mesothelial cells by activating HIF-1α. This finding indicates that hypoxia has pivotal roles in the development of peritoneal fibrosis in peritoneal dialysis patients.

Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10.

Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1ß, IL-6, transforming growth factor-ß1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.

ASC in renal collecting duct epithelial cells contributes to inflammation and injury after unilateral ureteral obstruction.

Inflammation plays a crucial role in the pathophysiological characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a multiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X7-potassium efflux and reactive oxygen species-dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.

Medication-prescribing patterns of primary care physicians in chronic kidney disease.

BACKGROUND: We investigated the medication-prescribing patterns of primary care physicians in chronic kidney disease (CKD). SUBJECTS AND METHODS: This cross-sectional study included 3,310 medical doctors who graduated from Jichi Medical University. The study instrument was a self-administered questionnaire to investigate their age group, specialty, workplace, existence of a dialysis center at workplace, and their prescription frequencies (high, moderate, low, very low) of the following agents--calcium (Ca) inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonist (ARBs), statins, anti-platelet agents, erythropoietin (Epo), AST-120, vitamin D, and sodium hydrogen carbonate (NaHCO(3)). RESULTS: From a total of 933 responses, 547 (61.0 %) medical doctors prescribed medication for CKD. The prescription frequencies of Ca inhibitors, ACEIs, and ARBs were high (>90 %, high + moderate), those of statins, anti-platelet agents, Epo, and AST-120 were moderate (90-50 %, high + moderate), and those of vitamin D and NaHCO(3) were low (<50 %, high + moderate). The primary care physician's specialty was significantly associated with their prescription frequency of Ca inhibitors (p < 0.01). Their workplace was significantly associated with their prescription frequency of ACEIs (p < 0.01), ARBs (p < 0.01), Epo (p < 0.01) and vitamin D (p < 0.01). The existence of a dialysis center at their workplace was significantly associated with their prescription frequency of Epo (p < 0.01), vitamin D (p < 0.01) and NaHCO(3) (p < 0.01). Their age was not associated with their prescription frequency of any agents. CONCLUSION: Antihypertensives were highly prescribed, and vitamin D and NaHCO(3) were less prescribed by primary care physicians for CKD. There were certain associations between the prescribing patterns of primary care physicians for CKD and their specialty, workplace and the existence of a dialysis center at their workplace.

Primary care physicians' own exercise habits influence exercise counseling for patients with chronic kidney disease: a cross-sectional study.

BACKGROUND: The appropriate exercise counseling for chronic kidney disease (CKD) patients is crucial to improve their prognosis. There have been few studies about exercise counseling by primary care physicians for CKD patients. We investigated primary care physicians' exercise counseling practices for CKD patients, and the association of these physicians' own exercise habits with exercise counseling. METHODS: The population of this cross-sectional study was 3310 medical doctors who graduated from Jichi Medical University from 1978 to 2012. The study instrument was a self-administered questionnaire that was mailed in August 2012 to investigate their age class, specialty, workplace, exercise habits, and practices of exercise counseling for CKD. RESULTS: 581 (64.8%) medical doctors practiced the management of CKD among a total of 933 responses. These 581 medical doctors were defined as CKD primary care physicians and their answers were analyzed. CKD primary care physicians' own exercise habits (frequencies and intensities) were as follows: frequencies: daily, 71 (12.1%); ≥ 2-3 times/week, 154 (26.5%); ≥ 1 time/week, 146 (25.1%); and ≤ 1 time/month, 176 (30.2%); intensities: high (≥ 6 Mets), 175 (30.1%); moderate (4-6 Mets), 132 (22.7%); mild (3-4 Mets), 188 (32.3%); very mild (<3 Mets), 47 (8.1%); and none, 37 (6.4%). The CKD primary care physicians' exercise recommendation levels for CKD patients were as follows: high, 31 (5.3%); moderate, 176 (29.7%); low, 256 (44.0%); and none, 92 (15.8%). The CKD primary care physicians' exercise recommendations for CKD patients were significantly related to their own exercise frequency (p < 0.001), but they were not related to their age, specialty, workplace, or exercise intensity. CONCLUSIONS: CKD primary care physicians' exercise recommendation level for CKD patients was limited. In addition, CKD primary care physicians' own exercise habits influenced the exercise counseling for CKD patients. The establishment of guidelines for exercise by CKD patients and their dissemination among primary care physicians are needed.(University Hospital Medical Information Network Clinical Trial Registry. number, UMIN000011803. Registration date, Sep/19/2013).

Patients with adult minimal change nephrotic syndrome treated with long-term cyclosporine did not experience a reduction in their eGFR.

BACKGROUND: The long-term efficacy and safety of cyclosporine (CyA) in the treatment of adult minimal change nephrotic syndrome (MCNS) was examined. METHODS: The medical record of 15 patients diagnosed with MCNS by renal biopsy and treated with CyA for at least 2 years were reviewed. RESULTS: The mean administration period of CyA was 78.3 months. The mean CyA dose for the induction period was 2.1 ± 0.9 mg/kg and 1.7 ± 1.0 mg/kg for the maintenance period. The mean dose of prednisolone used during the induction period was 20.3 mg and 2.7 mg during the maintenance. The frequency of MCNS relapse was decreased to 0.5 times/year in patients treated with CyA, compared to treatment without CyA (2.4 times/y). Two cases of mild liver damage and 3 cases of elevated blood pressure were observed during the administration of CyA. These adverse effects improved after reducing the CyA dose or treatment with an antihypertensive agent. A decrease in the estimated glomerular filtraion rate (eGFR) was not associated with long-term CyA use. CONCLUSION: At our institution, patients who were treated for MCNS with CyA for at least 2 years experienced no deterioration in renal function.

The origin of idiopathic renal arteriovenous malformation with giant twin aneurysms.

A 50-year-old female patient who presented with intermittent gross hematuria was referred to our hospital. Three-dimensional computed tomography (3D-CT) revealed a left renal arteriovenous malformation (AVM). Because she declined to undergo additional therapy including surgical treatment, we observed the clinical course of renal AVM for 7 years using 3DCT. When the 3D-CT showed gradual enlargement of the aneurysms concurrent with the onset of clinical symptoms (cardiomegaly and hypertension), we performed simple left nephrectomy. After the operation, the cardiomegaly and hypertension returned to normal, and gross hematuria did not recur. Based on the macro-anatomical findings of the resected kidney and the observation of the natural course, this case strongly supported the hypothesis that the renal AVM had existed from birth and enlarged gradually to eventually produce the typical signs and symptoms.

A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis.

IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63-year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease.

Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules.

Claudin-2 is highly expressed in tight junctions of mouse renal proximal tubules, which possess a leaky epithelium whose unique permeability properties underlie their high rate of NaCl reabsorption. To investigate the role of claudin-2 in paracellular NaCl transport in this nephron segment, we generated knockout mice lacking claudin-2 (Cldn2(-/-)). The Cldn2(-/-) mice displayed normal appearance, activity, growth, and behavior. Light microscopy revealed no gross histological abnormalities in the Cldn2(-/-) kidney. Ultrathin section and freeze-fracture replica electron microscopy revealed that, similar to those of wild types, the proximal tubules of Cldn2(-/-) mice were characterized by poorly developed tight junctions with one or two continuous tight junction strands. In contrast, studies in isolated, perfused S2 segments of proximal tubules showed that net transepithelial reabsorption of Na(+), Cl(-), and water was significantly decreased in Cldn2(-/-) mice and that there was an increase in paracellular shunt resistance without affecting the apical or basolateral membrane resistances. Moreover, deletion of claudin-2 caused a loss of cation (Na(+)) selectivity and therefore relative anion (Cl(-)) selectivity in the proximal tubule paracellular pathway. With free access to water and food, fractional Na(+) and Cl(-) excretions in Cldn2(-/-) mice were similar to those in wild types, but both were greater in Cldn2(-/-) mice after i.v. administration of 2% NaCl. We conclude that claudin-2 constitutes leaky and cation (Na(+))-selective paracellular channels within tight junctions of mouse proximal tubules.

Sex hormones induce a gender-related difference in renal expression of a novel prostaglandin transporter, OAT-PG, influencing basal PGE2 concentration.

Based on the nucleotide sequence of a mouse prostaglandin-specific transporter (mOAT-PG), we identified a rat homolog (rOAT-PG) which shares 80% identity with mOAT-PG in a deduced amino acid sequence. rOAT-PG transports PGE(2) and colocalizes with 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a metabolic enzyme for PGs, in proximal tubules, suggesting that rOAT-PG is involved in PGE(2) clearance to regulate its physiological function in the renal cortex. We found that the expression level of rOAT-PG in the renal cortex was much higher in male rats than in female rats whereas there was no gender difference in the expression level of cyclooxygenase-2, a key enzyme producing PGE(2), and 15-PGDH in the renal cortex. Tissue PGE(2) concentration in the renal cortex was lower in male rats than in female rats, suggesting that renocortical PGE(2) concentration is primarily determined by the expression level of OAT-PG, which is regulated differently between male and female rats. Castration of male rat led to a remarkable reduction in OAT-PG expression and a significant increase in renocortical PGE(2) concentration. These alterations were recovered by testosterone supplementation. These results suggest that OAT-PG is involved in local PGE(2) clearance in the renal cortex. Although the physiological importance of the gender difference in local PGE(2) clearance is still unclear, these findings might be a key to clarifying the physiological roles of PGE(2) in the kidney.

Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy.

To examine whether and how heart ANG II influences the coordination between cardiomyocyte hypertrophy and coronary angiogenesis and contributes to the pathogenesis of diabetic cardiomyopathy, we used Spontaneously Diabetic Torii (SDT) rats treated without and with olmesartan medoxomil (an ANG II receptor blocker). In SDT rats, left ventricular (LV) ANG II, but not circulating ANG II, increased at 8 and 16 wk after diabetes onset. SDT rats developed LV hypertrophy and diastolic dysfunction at 8 wk, followed by LV systolic dysfunction at 16 wk, without hypertension. The SDT rat LV exhibited cardiomyocyte hypertrophy and increased hypoxia-inducible factor-1α expression at 8 wk and to a greater degree at 16 wk and interstitial fibrosis at 16 wk only. In SDT rats, coronary angiogenesis increased with enhanced capillary proliferation and upregulation of the angiogenic factor VEGF at 8 wk but decreased VEGF with enhanced capillary apoptosis and suppressed capillary proliferation despite the upregulation of VEGF at 16 wk. In SDT rats, the phosphorylation of VEGF receptor-2 increased at 8 wk alone, whereas the expression of the antiangiogenic factor thrombospondin-1 increased at 16 wk alone. All these events, except for hyperglycemia or blood pressure, were reversed by olmesartan medoxomil. These results suggest that LV ANG II in SDT rats at 8 and 16 wk induces cardiomyocyte hypertrophy without affecting hyperglycemia or blood pressure, which promotes and suppresses coronary angiogenesis, respectively, via VEGF and thrombospondin-1 produced from hypertrophied cardiomyocytes under chronic hypoxia. Thrombospondin-1 may play an important role in the progression of diabetic cardiomyopathy in this model.

Development of features of glomerulopathy in tumor-bearing rats: a potential model for paraneoplastic glomerulopathy.

BACKGROUND: It has been well-recognized that cancer patients occasionally develop renal disorders independently of direct tumor invasion. However, the clinical entity of paraneoplastic glomerulopathy remains poorly understood, in part due to the lack of an animal model for basic research. In the present study, we investigated whether cancer-bearing rats develop features of glomerulopathy. METHODS: RCN-9 rat colon cancer cells (1 × 10(7)) were injected into F344 rats (n = 13) and T cell-deficient F344 rats (nude rats; n = 7) via the portal system. Urinalysis and histological examinations were performed in comparison with control rats (n = 6) that received a vehicle injection. RESULTS: Metastatic growth of RCN-9 cells exclusively in the liver was observed in the cancer-injected F344 rats, whereas direct invasion into the kidney was not evident even microscopically. Two of the cancer-injected F344 rats died within 2 days, but 9 of the 11 that avoided early death showed elevation of urinary protein (up to 158.0 mg/day) compared to controls (mean values: 60.8 ± 12.9 versus 17.8 ± 2.1 mg/day, P = 0.0291). Although morphological changes were not evident in light microscopy, abundant IgG in the glomerular tufts of the proteinuric rats was shown immunohistochemically. Ultrastructure analysis revealed electron-dense deposits in the glomerular basement membrane zone and effacement of the podocytic foot process. Interestingly, none of the nude rats showed proteinuria despite of cancer growth, suggesting that a specific immune response was involved. CONCLUSIONS: The tumor-bearing rats developed features of glomerulopathy, as expected from the clinical perspective, and this animal model may provide new insights into the development of paraneoplastic glomerulopathies.

Matrix metalloproteinase-2 inhibition by temocapril and its important role in peritoneal transport.

1. Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis (PD), but MMP-2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin-converting enzyme inhibitor (ACEI), can inhibit MMP-2. 2. To investigate the potential usefulness of ACEI during PD, the molecular interaction between the MMP-2 active site and the active form of temocapril (temocaprilat) was investigated using molecular modelling. Furthermore, the effects of temocapril on MMP-2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. 3. Temocaprilat bound to the MMP-2 active centre and recognized two hydrophobic substrate-binding sites in the MMP-2 molecular model. Matrix metalloproteinase-2 activity in peritoneal effluents was directly inhibited by temocaprilat (IC(50) 0.47 µmol/L). In one patient given temocapril, the peritoneal solute transport rate decreased gradually during PD. 4. Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP-2 inhibition to prevent peritoneal injury caused by PD.