[Tuberculosis of the thyroid gland mimicking thyroid carcinoma in the elderly].

A 76-year-old woman with a 10-year history of chronic glomerulonephritis was treated at a clinic after presenting with a gradual worsening of the renal function. The patient had no history of tuberculosis. She was subsequently hospitalized for uremic symptoms and treated with internal shunt insertion and dialysis. Thyroid ultrasonography was performed to screen for secondary hyperparathyroidism, which revealed a calcified thyroid mass and cervical lymph node swelling. Fine-needle aspiration biopsy was thus conducted to assess suspected thyroid cancer. The cytological findings showed few follicular epithelial cells, without any signs of malignancy. However, a diagnosis of thyroid cancer continued to be strongly suspected based on the imaging features. Total thyroidectomy and bilateral cervical regional lymph node dissection were therefore performed, and the pathological examination of the thyroidectomy specimen disclosed scattered epithelioid granulomas with caseous necrosis in the entire right lobe as well as the cervical lymph nodes. Based on these findings, the patient was diagnosed with thyroid tuberculosis. As the symptoms and imaging findings of tuberculosis are nonspecific in elderly patients, it is necessary to consider this disease in this population. We therefore propose the inclusion of thyroid tuberculosis in the differential diagnosis of elderly patients who present with malignant thyroid tumors on aspiration biopsy cytology, regardless of whether or not they have a previous history of tuberculosis.

[Fulminant type 1 diabetes in an elderly patient treated after receiving a diagnosis of type 2 diabetes].

The patient was a 76-year-old, male who was diagnosed with high blood glucose at 30 years of age. He suffered a stroke at 52 years of age. and was diagnosed with type 2 diabetes at a nearby hospital. Oral hypoglycemic medicines were administered along with diet and exercise therapy, which resulted in good glycemic control. The patient required an emergency hospital admission in December 2010 for weight loss. In addition, he suffered from frequent urination. He was diagnosed with diabetic ketoacidosis based on the following findings: blood glucose, 1,003 mg/dL; glycated hemoglobin, 7.7%; positive urine ketone bodies; and blood gas pH, 7.293. Although he had previously received medical treatment, the patient was transferred to our hospital, as he was unable to achieve stable glycemic control. At the time of admission, level of blood glucose and fasting serum C peptide were 1.002 mg/dL and 0.1 ng/mL, respectively. A glucagon loading test performed at our hospital revealed a serum C peptide level of <0.5 ng/ml. Tests for islet-cell autoantibodies were negative, and the patient's pathological conditions met the diagnostic criteria for fulminant type 1 diabetes. His human leukocyte antigen genotype was DRB1*0405 DQB1*0401, which is a disease susceptibility haplotype. In our experience, acute exacerbation of fulminant type 1 diabetes is observed in elderly patients who receive treatment following a diagnosis of type 2 diabetes. The differential diagnosis of ketoacidosis in elderly patients with type 2 diabetes should also include fulminant type 1 diabetes. Furthermore, providing an appropriate diagnosis and rapid treatment intervention is required.

[Incidence and clinical outcome of contrast-induced nephropathy in the elderly patients].

BACKGROUND: Aging is an established risk factor for contrast-induced nephropathy (CIN). However, little information is available on the incidence and clinical outcome of CIN for the elderly patients in Japan. OBJECTIVES: We determined the incidence and clinical outcome of CIN in the Japanese elderly patient. METHODS: We studied 292 patients who had mild renal dysfunction (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) at baseline and underwent coronary angiography. Patients were divided into two groups base on their age: the elderly group (age ≥ 75, n=108) and the control group (age<75, n=184). CIN was defined as a 25% increase in serum creatinine or an increase in serum creatinine by>0.5 mg/dl above the baseline value at or within 2 days post procedure. RESULTS: Patients in the elderly group had a higher incidence of CIN (14%) than those in the control group (9%). In patients who developed CIN, there was no significant difference between the two groups in baseline GFR and GFR on days 1, 2, 7 and 30 after the procedure. However, the relative increase in GFR above baseline on day 7 (-4.0 ± 6.1 vs -8.3 ± 8.0 ml/min P=0.096) and day 30 (1.5 ± 9.4 vs -10.1 ± 9.6 ml/min P=0.0017) in the elderly group was higher than that in the control group. Furthermore, death occurred in 3 patients in the elderly group (20%) whereas no patient died in the control group (P=0.092). CONCLUSION: Aging (age ≥ 75) is a risk factor for CIN in Japanese. CIN in the elderly patients may be associated with prolonged renal dysfunction and poor prognosis.

Activation of renal angiotensin type 1 receptor contributes to the pathogenesis of progressive renal injury in a rat model of chronic cardiorenal syndrome.

Although chronic cardiac dysfunction is known to progressively exacerbate renal injury, a condition known as type 2 cardiorenal syndrome (CRS), the mechanism responsible is largely unknown. The present study was undertaken to clarify the mechanism of renal injury in rats with both unilateral nephrectomy (NX) and surgically induced myocardial infarction (MI), corresponding to a model of type 2 CRS. Compared with a control group, rats with both MI and NX (MI+NX) exhibited progressive proteinuria during the experimental period (34 wk after MI surgery), whereas proteinuria was not observed in rats with MI alone and was moderate in rats with NX alone. The proteinuria in rats with MI+NX was associated with renal lesions such as glomerulosclerosis and infiltration of mononuclear cells and upregulation of the renal proinflammatory and -fibrotic cytokine and angiotensin II type 1a receptor (AT1aR) genes. In contrast, plasma renin activity was lowered in rats with MI+NX. Immunohistochemistry revealed that the increased AT1R protein was present mainly in renal interstitial mononuclear cells. Olmesartan medoxomil, an AT1R blocker, markedly reduced the proteinuria and infiltration of mononuclear cells, whereas spironolactone, a mineralocorticoid receptor blocker, did not. The present findings demonstrate the pathogenetic role of renal interstitial AT1R signaling in a model of type 2 CRS, providing evidence that AT1R blockade can be a useful therapeutic option for this syndrome.

Urinary liver-type fatty acid-binding protein level as a predictive biomarker of contrast-induced acute kidney injury.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a well-known complication of contrast medium exposure in patients with chronic kidney disease. However, there are no biological markers to accurately predict the onset of CI-AKI. Liver-type fatty acid-binding protein (L-FABP), an intracellular carrier protein for free fatty acids, is markedly upregulated and abundantly expressed in the proximal tubules after renal ischaemia. We prospectively investigated whether urinary L-FABP is a suitable marker for the prediction of CI-AKI. METHODS: We performed a prospective study of 220 consecutive patients with chronic kidney disease who underwent elective catheterization [serum creatinine (Cr) ≥ 1.2 mg/dL (106 M)]. Serum Cr and L-FABP levels were measured immediately before and 1 and 2 days after the procedure. CI-AKI was defined as an increase in serum Cr level of ≥ 0.3 mg/dL within 48 h after the procedure. RESULTS: We observed the development of CI-AKI in 19 patients (8.6%). Urinary L-FABP levels were significantly higher in patients with CI-AKI than those without CI-AKI before contrast medium exposure. Receiver operating characteristic analysis showed that baseline urinary L-FABP level exhibited 82% sensitivity and 69% specificity, at a cut-off value of 24.5 µg/g Cr. Using multivariate analysis, we found that independent predictors of CI-AKI development were L-FABP level of ≥ 24.5 µg/g Cr [odds ratio (OR): 9.10; 95% confidence interval (CI), 3.20-28.9], and left ventricular ejection fraction ≤ 40% (OR, 3.42; 95% CI, 1.07-10.8). CONCLUSIONS: Urinary L-FABP level is useful for predicting the onset of CI-AKI before contrast medium exposure.

Pharmacokinetics and administration method of gentamicin in a patient on haemodialysis.

We investigated the pharmacokinetics of gentamicin in a haemodialysis patient treated for endocarditis caused by methicillin-resistant Staphylococcus aureus and found that the administration of gentamicin immediately prior to dialysis was a suitable strategy for reaching target maximum drug concentration (Cmax) values and low trough levels.

Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.

A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.

A new protocol using sodium bicarbonate for the prevention of contrast-induced nephropathy in patients undergoing coronary angiography.

Contrast-induced nephropathy (CIN) is associated with increased morbidity and mortality rates. Although a previous study reported that pretreatment with sodium bicarbonate is more effective than sodium chloride for prophylaxis of CIN, this has not been a universal finding. We performed a prospective randomized trial to investigate whether CIN can be avoided using sodium bicarbonate. In total 155 patients with a glomerular filtration rate (GFR) <60 ml/min/1.73 m(2) who were undergoing coronary angiography were enrolled. We assigned patients to sodium chloride plus sodium bicarbonate (bicarbonate group, n = 78) or sodium chloride alone (chloride group, n = 77). Infusion of sodium bicarbonate at 1 ml/kg/hour continued from 3 hours before to 6 hours after coronary angiography. CIN was defined as a 25% increase in serum creatinine from baseline value or an absolute increase of ≥0.5 mg/dl, which appeared within 2 days of contrast. Baseline GFR was not significantly different between the 2 groups. Patients in the bicarbonate group had a higher GFR than those in the chloride group on day 2 (45.8 ± 13.4 vs 40.9 ± 14.6 ml/min/1.73 m(2), p = 0.031) and at 1 month (49.5 ± 14.7 vs 43.7 ± 15.5 ml/min/1.73 m(2), p = 0.019). CIN occurred in 10 patients (13%) in the chloride group but in only 2 patients (2.6%) in the bicarbonate group (p = 0.012). Sodium chloride plus sodium bicarbonate is more effective than sodium chloride alone for prophylaxis of CIN and can lead to retention of better long-term renal function.

Contrast-induced nephropathy in patients undergoing emergency percutaneous coronary intervention for acute coronary syndrome.

Contrast-induced nephropathy (CIN) is associated with significantly increased morbidity and mortality after coronary angiography and percutaneous coronary intervention (PCI). The aim of the present study was to assess the clinical features and in-hospital outcomes of CIN after emergency PCI. The serum creatinine (SCr) concentration was measured from days 0 to 30 in 338 consecutive patients with acute coronary syndrome undergoing emergency PCI. CIN was defined as an increase in SCr of >25% or >0.5 mg/dl within 2 days after PCI. Overall, 94 patients (28%) developed CIN. The mean SCr on admission was not significantly different between patients with CIN and those without CIN. The CIN group had significantly greater SCr at days 1, 2, and 30 than did the no CIN group. Multivariate analysis showed female gender (odds ratio [OR] 2.38, 95% confidence interval [CI] 1.12 to 5.07, p = 0.025), a culprit lesion in the left anterior descending artery (OR 2.37, 95% CI 1.31 to 4.27, p = 0.0042), contrast agent volume >200 ml (OR 3.60, 95% CI 1.96 to 6.62, p <0.001) and end-diastolic pulmonary arterial pressure >15 mm Hg (OR 2.03, 95% CI 1.02 to 4.04, p <0.01) to all correlate independently with CIN. The in-hospital mortality rate was greater in the CIN group than in the no CIN group (9.6% vs 3.3%, respectively; p = 0.025). In conclusion, CIN is a frequent complication of emergency PCI for acute coronary syndrome and is associated with a greater mortality rate and persistent renal dysfunction.

Prevention of contrast-induced nephropathy by chronic pravastatin treatment in patients with cardiovascular disease and renal insufficiency.

BACKGROUND: Contrast-induced nephropathy (CIN) is known to increase morbidity and mortality of cardiovascular disease. Recent studies have shown statins prevented CIN after contrast media exposure, but optimal statin type and dosage are still unknown. PURPOSE: The aims of the present study were to evaluate whether chronic pravastatin treatment before scheduled coronary angiography or percutaneous coronary intervention could reduce the incidence of CIN and to elucidate the factors related to CIN in patients with renal insufficiency. METHODS: We studied 431 consecutive patients with renal insufficiency. One hundred ninety-four patients were receiving pravastatin treatment as standard chronic treatment of hypercholesterolemia. Serum creatinine levels were measured at baseline (pre-procedure) and within 48 h after contrast media exposure (peak post-procedure). CIN was defined as an increase in the serum creatinine values of > or = 25% or > or = 0.5 mg/dl after contrast media exposure. Logistic regression analysis was performed to evaluate the important factors related to CIN using four variables: age, pravastatin, pre-procedure serum creatinine, and contrast volume. RESULTS: CIN was observed in 36 patients (8.4%). Patients without pravastatin (p<0.01), high level pre-procedure serum creatinine (p<0.01), and high contrast volume (p=0.034) had a significantly higher incidence of CIN. Logistic regression analysis revealed that pravastatin treatment (chi(2)=6.549, p=0.011, odds ratio=0.34), pre-procedure serum creatinine (chi(2)=6.294, p=0.009, odds ratio=2.78), and contrast volume (chi(2)=4.484, p=0.034, odds ratio=1.01) were independently related to the decreased risk of CIN. CONCLUSIONS: Chronic pravastatin treatment before contrast media exposure was important for preventing CIN in patients with renal insufficiency. Also, reducing the dose of contrast media was important for preventing CIN in patients with high-baseline serum creatinine levels.

Adiponectin incompletely prevent MCP-1-dependent restenosis after percutaneous coronary intervention [corrected] in patients with coronary artery disease.

BACKGROUND: Some factors play pathogenic roles in the development of restenosis after percutaneous coronary intervention (PCI). We measured and compared the ratio of elevated levels of monocytic chemotactic peptide-1 (MCP-1), regulated on activation normally T-cell expressed and secreted (RANTES), soluble (s) P-selectin, sE-selectin and adiponectin after PCI. METHODS: Plasma levels of chemokines and soluble markers were measured before and 30 days after PCI in 96 patients (69 males and 27 females, aged 63 +/- 9 years) who underwent PCI and who had repeated angiograms at a 6-month follow-up. In addition, we carried out the basic study of the tissue factor expression on monocytic cell line (THP-1) by MCP-1. RESULTS: Restenosis occurred in 33 (34.4%) patients. A significant and time-dependent increase in MCP-1 was observed in the restenosis group. However, there were no significant differences in RANTES, sP-selectin, and sE-selectin levels with or without restenosis. Adiponectin levels in patients with coronary artery disease were significantly lower than levels in normal controls. However, adiponectin levels were no different at baseline between patients with or without restenosis. MCP-1 did not induce the expression of tissue factor on THP-1. However, the recombinant sCD40 ligand-induced expression of tissue factor on THP-1 was enhanced by the addition of MCP-1. CONCLUSION: These findings suggest that restenosis development after PCI in patients with coronary artery disease may involve the participation of MCP-1 after PCI, and adiponectin incompletely prevent this MCP-1-dependent restenosis.

Ca(2+)-dependent glycolysis activation mediates apoptotic ATP elevation in HeLa cells.

It was previously shown that cells die with increased cytosolic ATP after stimulation with apoptotic inducers including staurosporine (STS). To identify the source of apoptotic ATP elevation, we monitored, in real time, the cytosolic ATP level in luciferase-expressing HeLa cells. A mitochondrial uncoupler or a respiration chain inhibitor was found to decrease cytosolic ATP by about 50%. However, even when mitochondrial ATP synthesis was suppressed, STS induced a profound elevation of intracellular ATP. In contrast, the STS-induced ATP increase was prevented by any of three inhibitors of the glycolytic pathway: 2-deoxyglucose, iodoacetamide, and NaF. The STS effect strongly depended on intracellular calcium and was mimicked by a calcium ionophore. We conclude that Ca(2+)-dependent activation of anaerobic glycolysis, but not aerobic mitochondrial oxidative phosphorylation, is responsible for the STS-induced elevation of ATP in apoptotic HeLa cells.

Platelet-derived chemokine RANTES may be a sign of restenosis after percutaneous coronary intervention in patients with stable angina pectoris.

Inflammation plays a pathogenic role in the development of restenosis after percutaneous coronary intervention (PCI). We measured and compared the ratio of elevated levels of regulated on activation normally T-cell expressed and secreted (RANTES), monocytic chemotactic peptide-1 (MCP-1), soluble (s) P-selectin and sL-selectin after PCI. Plasma levels of chemokines and soluble markers were measured before, 1, 3 and 7 days after PCI in 52 patients (43 males and nine females, aged 63 +/- 10 years) who underwent PCI and who had repeated angiograms at a 6-month follow-up. Restenosis occurred in 16 (31%) patients. A significant and time-dependent increase in sL-selectin was observed in the restenosis group. However, there were no significant differences in MCP-1 levels with or without restenosis. sP-selectin levels in the restenosis group exhibited a transient elevation at 3 days after PCI. RANTES levels were no different at baseline between patients with or without restenosis. However, a significant and time-dependent decrease in RANTES levels were observed in the non-restenosis group, and patients with restenosis compared with patients without restenosis had a statistically significant ratio of elevated levels of RANTES. These findings suggest that restenosis development after PCI in patients with effort angina pectoris may involve leukocyte activation at an early period after PCI. In addition, platelet-derived chemokine RANTES may be a sign of restenosis after PCI in patients with stable angina pectoris.

[Hypoadiponectinemia implies the development of atherosclerosis in carotid and coronary arteries].

OBJECTIVES: Adiponectin is an adipocyte-derived endocrine factor. Hypoadiponectinemia has been observed in obese patients, and plasma adiponectin levels are reported to increase during weight reduction. Moreover, hypoadiponectinemia has also been observed in patients with coronary artery diseases. The present study investigated the relationships between levels of adiponectin and carotid intimal-medial thickness, a marker of early vascular disease, and carotid artery plaque and the severity of coronary artery disease, a marker of advanced vascular disease. METHODS: Four hundred thirty-one consecutive patients were enrolled from inpatients without acute coronary syndrome who underwent coronary angiography between August 2001 and August 2003. The residual adiponectin levels were calculated by adjusting for sex, age, and body mass index, and a logarithmic transformation was applied. The severity of coronary artery disease was evaluated by coronary angiography and divided into four groups (Group 0: no significant organic stenosis, Group 1: 1-vessel disease, Group 2: 2-vessel disease, Group 3: 3-vessel disease or left main coronary trunk disease). Carotid plaque was evaluated by ultrasonography and divided into two groups [Group(-) : patients without carotid plaque, Group (+): patients with carotid plaque]. The intimal-medial thickness was measured on a longitudinal scan of the common carotid artery at a point 1 cm proximal from the bifurcation bulb. RESULTS: The logarithmic-transformed levels of residual adiponectin were associated with severity of coronary artery disease (Group 0: 0.18 +/- 0.59 microg/ml, Group 1: -0.02 +/- 0.56 microg/ml, Group 2: - 0.09 +/- 0.58 microg/ml, Group 3: - 0.10 +/- 0.66 microg/ml, p = 0.0013). The logarithmic-transformed levels of residual adiponectin were decreased in patients with carotid plaque [Group (-): 0.08 +/- 0.59 microg/ml, Group (+): - 0.08 +/- 0.59 microg/ml, p = 0.045]. However, the logarithmic-transformed levels of residual adiponectin were not associated with intimal-medial thickness (p = 0.6398). CONCLUSIONS: Hypoadiponectinemia adjusted for sex, age, body mass index implies the progression of carotid and coronary sclerosis.

Regulatory volume increase after secretory volume decrease in colonic epithelial cells under muscarinic stimulation.

To address the question of whether colonic secretory cells change their volume in response to carbachol (CCh) stimulation and, if so, the mechanisms involved therein, we used two-photon laser scanning microscopy to measure the volume of individual epithelial cells in the fundus region of crypts isolated from the guinea-pig distal colon. We also measured the volume of human colonic epithelial T84 cells using an electronic sizing technique. Both types of colonocytes responded to stimulation by CCh with shrinkage and then underwent a regulatory volume increase (RVI), even during continued stimulation by CCh. The secretory volume decrease (SVD) induced by CCh was antagonized by atropine, BAPTA loading and niflumic acid, a blocker of Ca(2+)-activated Cl(-) channels. An increase in the intracellular free [Ca(2+)] was observed with fura-2 during these volume responses to CCh. Removal of all Na(+) or K(+) or of most of the Cl(-) from the extracellular solution abolished the RVI, but not the preceding SVD. The RVI, but not the preceding SVD, was abolished by bumetanide, a blocker of the Na(+)-K(+)-2Cl(-) cotransporter. We conclude that guinea-pig crypt colonocytes and human T84 cells exhibit a cytosolic Ca(2+)-dependent SVD and undergo a subsequent RVI that is dependent on the operation of Na(+)-K(+)-2Cl(-) cotransporters.

Dual roles of plasmalemmal chloride channels in induction of cell death.

Even under anisotonic conditions, most cells can regulate their volume by mechanisms called regulatory volume decrease (RVD) and increase (RVI) after osmotic swelling or shrinkage, respectively. In contrast, the initial processes of necrosis and apoptosis are associated with persistent swelling and shrinkage. Necrotic volume increase (NVI) is initiated by uptake of osmolytes, such as Na+, Cl- and lactate, under conditions of injury, hypoxia, ischaemia, acidosis or lactacidosis. Persistence of NVI is caused by dysfunction of RVD due to impairment of volume-sensitive Cl- channels under conditions of ATP deficiency or lactacidosis. Both lactacidosis-induced RVD dysfunction and necrotic cell death are prevented by pretreatment of cells with the vacuolating cytotoxin-A (VacA) toxin protein purified from Helicobacter pylori, which forms a lactacidosis-resistant anion channel. Apoptotic volume decrease (AVD) is triggered by activation of K+ and Cl- conductances following stimulation with a mitochondrion-mediated or death receptor-mediated apoptosis inducer. Apoptotic cell death can be prevented by blocking the Cl- channels but not the K+-Cl- cotransporters. Thus, the volume regulatory anion channel plays, unless impaired, a cell-rescuing role in the necrotic process by ensuring RVD after swelling induced by necrotic insults, whereas normotonic activation of the anion channel plays a cell-killing role in the apoptotic process by triggering AVD following stimulation with apoptosis inducers.

[Infective endocarditis complicating bilateral bacterial ophthalmitis: a case report].

A 53-year-old female suddenly went blind in her left eye on 3 June, 2000. She was admitted to the Department of Ophthalmology of our hospital under the diagnosis of endophthalmitis. Her left eye was enucleated, and Streptococcus agalactiae was found in the vitreous fluid. After left ophthalmectomy, inflammation recurred after cessation of antibiotic administration. Echocardiography demonstrated a vegetation of the posterior mitral valve. The diagnosis was infective endocarditis. She was transferred to the Department of Internal Medicine. Mitral regurgitation deteriorated during the course of medical therapy, but she was discharged on 13 September, 2000 because inflammation had improved remarkably and the vegetation had disappeared after administration of penicillin G, panipenem, cefotaxime and clindamycin. We suspected that embolism of the ophthalmic artery was the cause of the sudden blindness in her left eye. Infective endocarditis with bacterial endophthalmitis is very rare in Japan.

Macula densa cell signaling involves ATP release through a maxi anion channel.

Macula densa cells are unique renal biosensor cells that detect changes in luminal NaCl concentration ([NaCl](L)) and transmit signals to the mesangial cellafferent arteriolar complex. They are the critical link between renal salt and water excretion and glomerular hemodynamics, thus playing a key role in regulation of body fluid volume. Since identification of these cells in the early 1900s, the nature of the signaling process from macula densa cells to the glomerular contractile elements has remained unknown. In patch-clamp studies of macula densa cells, we identified an [NaCl](L)-sensitive ATP-permeable large-conductance (380 pS) anion channel. Also, we directly demonstrated the release of ATP (up to 10 microM) at the basolateral membrane of macula densa cells, in a manner dependent on [NaCl](L), by using an ATP bioassay technique. Furthermore, we found that glomerular mesangial cells respond with elevations in cytosolic Ca(2+) concentration to extracellular application of ATP (EC(50) 0.8 microM). Importantly, we also found increases in cytosolic Ca(2+) concentration with elevations in [NaCl](L), when fura-2-loaded mesangial cells were placed close to the basolateral membrane of macula densa cells. Thus, cell-to-cell communication between macula densa cells and mesangial cells, which express P2Y(2) receptors, involves the release of ATP from macula densa cells via maxi anion channels at the basolateral membrane. This mechanism may represent a new paradigm in cell-to-cell signal transduction mediated by ATP.