Although an improvement of insulin sensitivity has been shown to be a new therapeutic approach for treating diabetes mellitus, details of effects of this treatment on the cardiovascular system and possible renal complications remain unknown. In the present study, we investigated the effects of a thiazolidine derivative, pioglitazone, and examined the insulin-sensitizing action on blood pressure, nephropathy, and vascular changes in genetically obese diabetic Wistar fatty (WF) rats. Pioglitazone (3 mg.kg-1.day-1) was orally administered for 13 wk starting at the age of 5 wk, and the results were compared with those of vehicle-treated WF rats. At the age of 18 wk, vehicle-treated WF rats were associated with mild hypertension, nephropathy with proteinuria histological glomerular injury, and renal arteriolosclerosis in addition to hyperglycemia, hyperinsulinemia, and hyperlipidemia. Treatment with pioglitazone significantly improved glucose and lipid metabolism. In addition, it lowered blood pressure, decreased proteinuria, and prevented glomerular injury, renal arteriolosclerosis, and aortic medial wall thickening, whereas body weight, food intake, sodium balance, and urinary norepinephrine excretion were significantly increased. These results suggest that the insulin-sensitizing agent pioglitazone is effective in correcting not only glucose and lipid metabolism but also cardiovascular and renal complications in non-insulin-dependent diabetes mellitus.

No abstract

No abstract

To elucidate the intracellular localization of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human cardiac myocytes, an immunocytochemical study was carried out by a double immunogold technique using antisera highly specific for ANP and BNP. Surgical and autoptic tissue specimens of human heart were studied. In the atrial myocytes, ANP was localized in almost all of the secretory granules, whereas BNP was colocalized with ANP in some of the granules. Although very few secretory granules were observed in ventricular myocytes, colocalization of ANP and BNP was basically the same as in atrial myocytes. No immunoreactive products were found in the control studies. These results suggest that secretion of BNP is under a regulatory mechanism similar to that of ANP.

The location of renin (EC 3.4.99.19) in rat pituitary was determined by the peroxidase-antiperoxidase immunohistochemical technique. By using antisera prepared with purified rat renal renin, an immunoreactive substance was localized within ovoid cells scattered throughout the anterior pituitary. These cells were shown to be luteinizing hormone-producing cells by staining with anti-luteinizing hormone antisera in adjacent sections. By using the double staining method, the renin-containing cells were differentiated from cells containing corticotropin, thyrotropin, growth hormone (somatotropin), and prolactin (mammotropin). These results suggest a possible local role for renin in the anterior pituitary.Renin (EC 3.4.99.19) (5), while a large amount ofprotease with nonspecific renin-like activity is found in both the anterior and the posterior lobes (unpublished data). Furthermore, in our immunohistochemical studies of the pituitary of the mouse (7) and rat (8), renin-specific staining was observed only in the anterior lobes.A similar lack of agreement is apparent among previous reports with respect to the intrahypophysial localization of angiotensin (9, 10). The consideration of the physiological function of a renin-angiotensin system in the pituitary has been largely focused on the posterior pituitary, presumably in association with the well-known effect of angiotensin II on vasopressin release (11), though the effect may not be exerted in the pituitary. The effect ofangiotensin II on the release ofadrenocorticotropic hormone (ACTH; corticotropin) from the anterior pituitary is also known (12), but the physiological role ofpituitary renin has remained unclear.With the objectives of resolving the existing controversies concerning the location of renin and obtaining clues for the physiological significance of renin in the pituitary, we have applied an immunohistochemical staining technique for the identification of the renin-containing cells in the pituitary.MATERIALS AND METHODS Antisera. Specific antibodies to rat renin were produced in Dutch Belted rabbits by using pure rat renin as antigen. The pure renin was prepared by a published method (13). The enzyme preparation satisfied multiple criteria ofpurity, which included single bands upon polyacrylamide gel electrophoresis, sodium dodecyl sulfate gel electrophoresis, isoelectric focusing, and double immunodiffusion and symmetric chromatographic elution patterns. This preparation (1.0 mg) was conjugated to 0.5 mg of tetanus toxoid with 25 ,ug of water-soluble carbodiimide and exhaustively dialyzed, and then an aliquot containing 80 ug of renin was mixed with an equal volume of complete Freund's adjuvant and injected intradermally at multiple sites in the back ofeach rabbit. After six biweekly boosters, each with the conjugate equivalent of 10 ,.g of renin, antisera were collected. Tested at dilutions greater than 1:500, these antibodies did not crossreact with human renin or rat cathepsin. Used at 1:2000 dilution for immunohistochemical staining of ra...

These results suggest that plasma ET-1 is related to diabetic microvascular disease.

We investigated the action of a synthetic rat atrial natriuretic factor (ANF) with 28 amino acids on renin secretion in rats. Renin release by kidney cortex slices was determined after 90 min of incubation at 37C. ANF inhibited basal renin release in a dose-related fashion. ANF also decreased cAMP release and increased cGMP release in a dose-dependent manner. Renin release stimulated by 10(-7) M isoproterenol was inhibited by ANF with an ID50 of 5.8 x 10(-8) M. The renin-inhibitory effect was not calcium-dependent. In anesthetized rats, a bolus IV dose of ANF decreased plasma renin activity and cAMP concentration, but increased cGMP concentration. These data suggest that ANF inhibits renin secretion via the direct action on juxtaglomerular cells and that this effect may be partly mediated by the changes in cyclic nucleotide production.

Readily detectable levels of renin activity were demonstrated in human adrenal tissues. This activity was inhibited by specific antibody raised against pure renin, indicating that it was not due to the nonspecific action of proteases. The renin activity was predominantly in the cortex rather than in the medulla of the adrenal. An adrenal gland that was surgically removed from a patient with Cushing's disease and had high renin activity was used for further characterization of the enzyme. It shared many biochemical features with kidney renin, such as molecular weight, isoelectric point, glycoprotein nature, optimum pH of enzyme activity, affinity to pepstatin, and the presence of trypsin-activatable inactive renin. The lack of correlation between PRA and the adrenal renin, and the particulate localization of the subcellular distribution of adrenal renin suggested its local origin rather than contamination or contribution of the plasma enzyme.