Michiaki Okumura

Effect of adrnomedullin on renal hemodynamics and functions in dogs

In order to elucidate the role of adrenomedullin in the kidney, we investigated the effects of adrenomedullin on renal hemodynamics and urine formation in anesthetized dogs. Intrarenal arterial infusion of adrenomedullin (0.8, 4 and 20 ng.kg-1.min-1) elicited dose-dependent increases in renal blood flow (by 10, 26 and 37%, respectively) with no change in blood pressure or heart rate, indicating a renal vasodilatory action of adrenomedullin. The glomerular filtration rate did not increase with the lower two doses, but increased marginally by 9% at the highest dose. Infusion of adrenomedullin at the rates of 4 and 20 ng.kg-1.min-1 increased urine flow and the urinary excretion of sodium and potassium dose dependently. Arterial and renal venous plasma renin activity was unaffected by adrenomedullin. These findings indicate that adrenomedullin is a potent renal vasodilatory peptide with a diuretic action. Since the threshold for the renal vasodilatory action of adrenomedullin is close to its physiological concentration in human plasma, adrenomedullin may play an important role in the regulation of renal function.

Attenuation of adrenomedullin-induced renal vasodilatation by NG-nitro L-arginine but not glibenclamide

1 The present study was conducted in order to elucidate the in vivo contribution of nitric oxide (NO) and the glibenclamide‐sensitive potassium channel in the renal action of adrenomedullin in anaesthetized dogs. 2 Intrarenal arterial infusion of adrenomedullin (20 ng kg−1 min−1) elicited a pronounced increase in renal blood flow with no changes in systemic blood pressure. The renal vasodilator action of adrenomedullin was markedly attenuated by pretreatment with NG–nitro L‐arginine (L‐NOARG), but this was reversed by continuous infusion of L‐arginine. 3 Pretreatment with glibenclamide almost completely blocked the renal vasodilatation induced by lemakalim, but had no effect on the renal vasodilator and diuretic action of adrenomedullin. 4 Intrarenal arterial infusion of adrenomedullin induced diuresis and natriuresis. Diuretic and natriuretic action of adrenomedullin was also attenuated by L‐NOARG. L‐Arginine partly reversed the effect of L‐NOARG and adrenomedullin‐induced diuresis and natriuresis. 5 These data indicate that the in vivo renal vasodilator action of adrenomedullin is mediated by the release of NO. The glibenclamide‐sensitive potassium channel is not involved in the renal action of adrenomedullin, at least, not in anaesthetized dogs. Since the inhibition of L‐NOARG of adrenomedullin‐induced diuresis occurred concomitantly with the attenuation of the renal vasodilator action of adrenomedullin, direct involvement of NO in adrenomedullin‐induced diuresis remains to be established.

Tonsillectomy has beneficial effects on remission and progression of IgA nephropathy independent of steroid therapy

BACKGROUND Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to examine the efficacy of tonsillectomy on remission and progression of IgA nephropathy. METHODS We conducted a single-center 7-year historical cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as disappearance of urine abnormalities at two consecutive visits, glomerular filtration rate (GFR) decline defined as 30% GFR decrease from baseline and GFR slope during the follow-up. RESULTS Seventy of the 200 patients received tonsillectomy. Tonsillectomy was associated with increased incidence of clinical remission (P+0.01, log-rank test) and decreased incidence of GFR decline (P=0.01, log-rank test). After adjustment for age and gender, hazard ratios in tonsillectomy were 3.90 (95% confidence interval 2.46-6.18) for clinical remission and 0.14 (0.02-1.03) for GFR decline. After further adjustment for laboratory (baseline mean arterial pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion, endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin-angiotensin system inhibitors), similar results were obtained in each model. Even after exclusion of 69 steroid-treated patients, results did not change. GFR slopes in tonsillectomy and non-tonsillectomy groups were 0.60±3.65 and -1.64±2.59 mL/min/1.73 m2/year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P=0.01). CONCLUSION Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration even in non-steroid-treated patients.

Strict angiotensin blockade prevents the augmentation of intrarenal angiotensin II and podocyte abnormalities in type 2 diabetic rats with microalbuminuria

Objectives Beneficial effects of angiotensin II type 1 receptor blockers have been indicated for patients with diabetic nephropathy. We investigated the effects of an angiotensin II type 1 receptor blocker, telmisartan, on intrarenal angiotensin II levels and the progression of albuminuria or glomerular injury in type 2 diabetic Otsuka Long–Evans Tokushima Fatty rats with microalbuminuria. Methods and Results Otsuka Long–Evans Tokushima Fatty rats were randomly treated with telmisartan (10 mg/kg/day, orally), hydralazine (25 mg/kg/day in drinking water) or vehicle from the initiation of albuminuria (13 weeks old). At this age, Otsuka Long–Evans Tokushima Fatty rats showed low but detectable albuminuria (1.0 ± 0.1 mg/day) and higher systolic blood pressure, postprandial blood glucose and kidney angiotensin II levels than age-matched nondiabetic Long–Evans Tokushima Otsuka rats. At 35 weeks of age, vehicle-treated Otsuka Long–Evans Tokushima Fatty rats did not show apparent glomerular injury or tubulointerstitial fibrosis but did exhibit severe albuminuria (72.6 ± 5.9 mg/day) and accumulation of cytoplasmic granules containing albumin in podocytes. Otsuka Long–Evans Tokushima Fatty rats also showed higher systolic blood pressure, postprandial blood glucose, collagen gene expression, desmin staining (a marker of podocyte injury) and angiotensin II levels than Long–Evans Tokushima Otsuka rats. Treatment with telmisartan did not affect postprandial blood glucose but decreased systolic blood pressure, collagen gene expression, desmin staining and angiotensin II levels. Telmisartan also prevented the development of albuminuria (0.6 ± 0.1 mg/day at 35 weeks old) and accumulation of cytoplasmic granules. Hydralazine treatment resulted in a similar reduction in systolic blood pressure and partially attenuated the albuminuria (35.4 ± 1.8 mg/day at 35 weeks old) but did not affect the other parameters. Conclusion The present results suggest the contribution of augmented intrarenal angiotensin II levels to the initiation and progression of albuminuria as well as podocyte abnormalities in type 2 diabetic rats. Angiotensin II blockade may inhibit the transition from microalbuminuria to overt nephropathy through prevention of intrarenal angiotensin II augmentation, independently of changes in blood pressure and glucose levels.

Mineralocorticoid Receptor Blockade Enhances the Antiproteinuric Effect of an Angiotensin II Blocker through Inhibiting Podocyte Injury in Type 2 Diabetic Rats

Treatment with angiotensin II type 1 receptor blockers (ARBs) is the first-line therapy for hypertensive patients with diabetic nephropathy. However, emerging clinical evidence indicates that mineralocorticoid receptor (MR) blockers have blood pressure-independent antiproteinuric effects. We sought to determine whether treatment with an MR blocker, eplerenone, enhances the effects of an ARB, telmisartan, on podocyte injury and proteinuria in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. From 20 to 50 weeks old, diabetic OLETF rats showed higher systolic blood pressure (SBP) and urinary protein excretion (UproteinV) than nondiabetic control Long-Evans-Tokushima-Otsuka rats. At 50 weeks old, OLETF rats also showed glomerular sclerosis and podocyte injury, whereas nephrin and podocin mRNA levels in isolated glomeruli were significantly decreased. Treatment with telmisartan (3 mg/kg/day p.o.) decreased SBP and UproteinV, increased nephrin and podocin mRNA levels, and attenuated glomerular sclerosis and podocyte injury. Eplerenone (100 mg/kg/day p.o.) did not alter SBP but elicited similar changes in renal parameters. However, greater reductions in UproteinV and podocyte injury and greater increases in nephrin and podocin mRNA levels were observed in the combination treatment group. Hydralazine (25 mg/kg/day p.o.) decreased SBP but did not alter any renal parameters. These data indicate that MR blockade enhances the SBP-independent antiproteinuric effect of an ARB through inhibiting podocyte injury in type 2 diabetic rats.

Putative mechanism of hypotensive action of platelet-activating factor in dogs

We examined the mechanism(s) of hypotensive action of platelet-activating factor (PAF) in anesthetized dogs. PAF (0.5 micrograms/kg i.v.) caused a biphasic hypotension; the first phase was transient and was accompanied by a decrease in systemic vascular resistance and an increase in cardiac output. Aspirin-DL-lysine, a cyclooxygenase inhibitor, had no effect on this phase. The second phase was characterized by a sustained hypotension caused by a reduction in cardiac output and was accompanied by an increase in systemic and pulmonary vascular resistance. The plasma concentrations of 6-ketoprostaglandin F1 alpha and thromboxane B2 also increased. These changes were markedly attenuated by aspirin. Both atrial pressures decreased during the second phase, thereby indicating that the PAF-induced reduction in cardiac output was related to a hindrance in venous return. The hematocrit increased, and aspirin did not affect this change. The extravasation of plasma probably plays a minor role, whereas venodilation would be the primary mechanism of the second-phase hypotension. S-1452, a prostaglandin H2/thromboxane A2 antagonist, abolished the PAF-induced pulmonary vasoconstriction but did not block the hypotensive action of PAF. OKY-046, a thromboxane A2 synthetase inhibitor, almost completely abolished the PAF-induced pulmonary vasoconstriction and the increase in plasma thromboxane B2 level, whereas it potentiated the hypotension and the increase in the plasma concentrations of prostaglandins; aspirin abolished this potentiation. These results suggest that PAF causes hypotension by two different mechanisms: 1) dilatation of resistance vessels independent of prostaglandins and 2) reduction of venous return due to venodilation, as mediated by prostaglandin(s).

Renal production of thromboxane and prostaglandins in a rat model of type 2 diabetes

In an investigation of the involvement of prostanoids in the pathogenesis of nephropathy in type 2 diabetes, we repeatedly measured the urinary excretion of prostanoids in both diabetic and healthy rats as the rats aged. Seven rats of the Otsuka Long-Evans Tokushima Fatty strain were used as rats with a model of type 2 diabetes and seven rats of the Long-Evans Tokushima Otsuka strain were used as rats without diabetes. Thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1alpha, the amounts of which reflect renal production of TXA2 and PGI2, respectively, and PGE2 in urine collected in metabolic cages were assayed when rats were 14, 30, 46, and 54 weeks old. Plasma glucose and urinary protein excretion also were measured periodically. The mean plasma glucose concentration of the diabetic rats was higher than that of the healthy rats throughout the study. At 30 weeks and later, urinary protein excretion by the diabetic rats was greater than that of the healthy rats, and it increased with age. Urinary excretion of TXB2 by the diabetic rats was higher than that of the healthy rats at 14 weeks (52.4+/-23.5 vs. 27.0+/-2.6 ng/day; mean +/- SD, P = .015) and the difference continued to the end of the experiment. Urinary excretion of 6-keto-PGF1alpha by the diabetic rats was high at 14 weeks (52.3+/-12.8 vs. 26.9+/-4.6 ng/day; mean +/- SD, P<.001) but decreased with age and was the same as that of the healthy rats at 54 weeks. The urinary excretion of PGE2 by the two groups of rats was not significantly different. These results suggest that altered renal production of TXA2 and PGI2 is involved in the pathogenesis of diabetic nephropathy in rats with type 2 diabetes.

Sodium Sensitivity of Blood Pressure Appearing Before Hypertension and Related to Histological Damage in Immunoglobulin A Nephropathy

Abstract—Patients with renal parenchymal disease exhibit sodium-sensitive hypertension. We examined patients with immunoglobulin A (IgA) nephropathy to determine whether this sensitivity appears before hypertension begins and whether this sensitivity is related to histological damage. Thirty-eight patients with IgA nephropathy followed a diet with an ordinary sodium level for 1 week and a sodium-restricted diet for 1 week, in random order, and were divided into 3 groups by their systemic blood pressure on the diet with an ordinary sodium level (optimal, <120/<80 mm Hg, n=15; normal to high-normal, 120 to 139/80 to 89 mm Hg, n=18; hypertensive, ≥140/≥90 mm Hg, n=5). The sodium sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linkage of 2 datum points obtained during the different diets. The scores for glomerulosclerosis and tubulointerstitial damage were evaluated semiquantitatively. The sensitivity index, glomerulosclerosis score, and score for tubulointerstitial damage were higher in patients with normal to high-normal blood pressure or hypertension than in patients with optimal pressure. The sensitivity index was significantly correlated with glomerulosclerosis (P =0.001) and tubulointerstitial damage (P =0.002). In patients with normal to high-normal pressure, sodium restriction lowered blood pressure to the optimal range and decreased proteinuria. In patients with IgA nephropathy, sodium sensitivity of blood pressure related to renal histological damage appears before hypertension.

Endothelin stimulates the renal production of prostaglandin E2 and I2 in anesthetized dogs

The infusion of endothelin into the renal artery of anesthetized dogs (5 ng/kg per min) decreased the renal blood flow without changing the blood pressure, indicating that endothelin caused renal vasoconstriction. The renal secretion rate of prostaglandin E2 and I2 markedly increased and these increases were abolished by pretreatment with aspirin. Furthermore, the renal vasoconstrictor effect of endothelin was potentiated by aspirin, suggesting a role of prostaglandins in the renal action of endothelin.

Role for thromboxane A2 from glomerular thrombi in nephropathy with type 2 diabetic rats.

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.