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      High Glucose Levels Alter Angiotensin II-Induced Ca 2+ Uptake via PKC and cAMP Pathways in Renal Proximal Tubular Cells

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          Abstract

          Although a dysfunction of the calcium metabolism occurs in diabetes mellitus, alterations of Ca<sup>2+</sup> uptake induced by angiotensin II (ANG II) in renal proximal tubular cells (PTCs) grown in high-glucose medium are not fully elucidated. Thus, we examined whether high glucose concentrations can induce an alteration of the ANG II effect on the Ca<sup>2+</sup> uptake and its action mechanism in primary cultured renal PTCs. PTCs were exposed to different glucose concentrations (5–100 m M) and time intervals (0–48 h). There was a sustained increase of Ca<sup>2+</sup> uptake at glucose concentrations >15 m M. Thus, we selected 25 m M glucose and incubation for 48 h to maintain a hyperglycemic condition in vitro, unlike short-time regulatin. ANG II significantly inhibited the Ca<sup>2+</sup> uptake in a dose-dependent manner in a 5-m M glucose medium. In addition, downregulation of ANG II receptors appeared in a glucose dose dependent manner. However, PTCs treated with 25 m M glucose for 48 h, not 12 h, did not exhibit the inhibitory effect of ANG II (10<sup>–7</sup>  M) on Ca<sup>2+</sup> uptake, although the inhibitory effect of ANG II on Ca<sup>2+</sup> uptake occurred in the presence of 25 m M mannitol or L-glucose. Staurosporine, bisindolylmaleimide I (protein kinase C, PKC, inhibitors), 12- o-tetradecanoylphorbol 13-acetate pretreatment, SQ 22536 (an adenylate cyclase inhibitor), and myristoylated protein kinase A inhibitor amide 14–22 (a protein kinase A inhibitor) blocked the 25-m M-glucose-induced alteration of ANG II effect on Ca<sup>2+</sup> uptake. These results suggest that both PKC and cyclic adenosine monophosphate (cAMP) pathways are involved in the high-glucose-induced alteration of ANG II effect on Ca<sup>2+</sup> uptake. Indeed, 25 m M glucose increased PKC activity and cAMP contents. In conclusion, a high glucose concentration altered ANG II induced inhibition of Ca<sup>2+</sup> uptake via PKC and cAMP pathways in the PTCs.

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          Diabetes mellitus: a disease of abnormal cellular calcium metabolism?

          Although the pathogenesis of the diabetes mellitus syndrome remains poorly understood, both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus predispose the individual to a similar spectrum of complications, including hypertension, macrovascular and microvascular disease, cataracts cardiomyopathy, neuropathy, and premature aging, suggesting that these complications develop along a pathway common to both diabetic conditions. Yet not all diabetic persons are affected by all of these complications or to the same degree. What causes this marked variability in the clinical manifestations of the diabetes syndrome remains an enigma. Accumulating data from animal models of diabetes and from studying patients with diabetes reveal that intracellular calcium levels are increased in most tissues. The activities of the membrane, adenosine triphosphatase (ATPase) associated cation pumps, which determine intracellular calcium level (i.e., calcium-ATPase and [sodium + potassium]-ATPase), are also altered. The nature of the alteration is often tissue specific and may depend on the level of blood glucose or insulin, or both. In this review we discuss the potential contribution of these changes in intracellular calcium regulation, whether acquired or genetically determined, to the pathogenesis of the diabetes syndrome, to the abnormalities in insulin secretion and action (mainly in non-insulin-dependent diabetes), and to the complications of both diabetes syndromes. Altered intracellular calcium metabolism may represent a common, underlying abnormality linking the metabolic, cardiovascular, ocular, and neural manifestations of the diabetic disease process.
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            Characterization of primary rabbit kidney cultures that express proximal tubule functions in a hormonally defined medium

            Primary cultures of rabbit-kidney epithelial cells derived from purified proximal tubules were maintained without fibroblast overgrowth in a hormone-supplemented serum-free medium (Medium RK-1). A hormone- deletion study indicated that the primary cultures derived from purified rabbit proximal tubules required all of the three supplements in Medium RK-1 (insulin, transferrin, and hydrocortisone) for optimal growth but did not grow in response to EGF and T3. In contrast, the epithelial cells in primary cultures derived from an unpurified preparation of rabbit kidney tubules and glomeruli grew in response to EGF and T3, as well as insulin, transferrin, and hydrocortisone. These observations suggest that kidney epithelial cells derived from different segments of the nephron grow differently in response to hormones and growth factors. Differentiated functions of the primary cultures derived from proximal tubules were examined. Multicellular domes were observed, indicative of transepithelial solute transport by the monolayers. The proximal tubule cultures also accumulated alpha- methylglucoside (alpha-MG) against a concentration gradient. However, little or no alpha-MG accumulation was observed in the absence of Na+. Metabolic inhibitor studies also indicated that alpha-MG uptake by the primaries is an energy-dependent process, and depends upon the activity of the Na+/K+ ATPase. Phlorizin at 0.1 mM significantly inhibited 1 mM alpha-MG uptake whereas 0.1 mM phloretin did not have a significant inhibitory effect. Similar observations have been made concerning the Na+-dependent sugar-transport system located on the lumenal side of the proximal tubule, whereas the Na+-independent sugar transporter on the peritubular side is more sensitive to inhibition by phloretin than phlorizin. The cultures also exhibited PTH-sensitive cyclic AMP synthesis and brush-border enzymes typical of proximal cells. However, the activities of the enzymes leucine aminopeptidase, alkaline phosphatase, and gamma-glutamyl-transpeptidase were lower in the cultures than in purified proximal-tubule preparations from which they are derived.
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              Interrupting the renin-angiotensin system: the role of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of hypertension.

              M A Weber (1999)
              The renin-angiotensin system has two roles in clinical hypertension: its vasoconstrictor properties directly govern blood pressure, and its actions on arterial smooth muscle, connective tissue, and endothelial integrity affect cardiovascular prognosis. Additionally, the direct actions of angiotensin II on the function and structure of the heart and renal vasculature influence clinical events. Angiotensin-converting enzyme (ACE) inhibitors have produced functional and clinical outcome benefits in clinical trials of patients with congestive heart failure, systolic dysfunction after myocardial infarction, and diabetic nephropathy. Similar favorable trends have been noted in observational studies in hypertension. Because such enzymes as chymase can substitute for ACE, the ACE inhibitors may not completely block angiotensin II formation, although they enhance bradykinin accumulation and secondarily stimulate nitric oxide and vasodilatory prostaglandins. Angiotensin II receptor blockers (ARB) selectively block the angiotensin II type 1 (AT1) receptor that not only mediates the known effects of angiotensin II but, according to recent reports, might be responsible for sequestering angiotensin II molecules in renal and cardiac cells. Moreover, by increasing plasma concentrations of angiotensin II, the ARB stimulate the unblocked angiotensin II type 2 (AT2) receptors, which-if they exist in meaningful numbers in human hypertension-mediate additional vasodilatory and antiproliferative effects. The contrasting actions of these two classes of drugs might be clinically relevant. For example, they may have additive antihypertensive efficacy; they have differing effects on renal plasma flow; and in a small pilot study of patients with congestive heart failure, the ARB demonstrated an apparent advantage in survival. Ongoing clinical trials will try to determine whether the effects of ARB can equal or even exceed the beneficial effects of ACE inhibitors on cardiovascular prognosis.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2001
                2001
                29 June 2001
                : 24
                : 2
                : 84-91
                Affiliations
                College of Veterinary Physiology, Hormone Research Center, Chonnam National University, Kwangju, Korea
                Article
                54212 Kidney Blood Press Res 2001;24:84–91
                10.1159/000054212
                11435739
                9c98242b-61a3-4acf-abde-f05643f95816
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 5, Tables: 2, References: 42, Pages: 8
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Glucose,Kidney,Protein kinase C,Cyclic adenosine monophosphate,Calcium,Angiotensin II

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