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      Adenosine A 1 Receptors Determine Glomerular Hyperfiltration and the Salt Paradox in Early Streptozotocin Diabetes Mellitus

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          Abstract

          Background: In early type 1 diabetes mellitus, changes in proximal reabsorption influence glomerular filtration rate (GFR) through tubuloglomerular feedback (TGF). Due to TGF, a primary increase in proximal reabsorption causes early diabetic hyperfiltration, while a heightened sensitivity of the proximal tubule to dietary salt leads to the so-called salt paradox, where a change in dietary salt causes a reciprocal change in GFR (‘tubulocentric principle’). Here, experiments were performed in adenosine A<sub>1</sub> receptor knockout mice (A<sub>1</sub>R–/–), which lack an immediate TGF response, to determine whether A<sub>1</sub>Rs are essential for early diabetic hyperfiltration and the salt paradox. Methods: GFR was measured by inulin disappearance in conscious A<sub>1</sub>R–/– and wild-type (WT) mice after 4 weeks of streptozotocin diabetes on a control NaCl diet (1%), and measurements were repeated after 6 days of equilibration on a low-NaCl (0.1%) or a high-NaCl (4%) diet. Results: A<sub>1</sub>R–/– and WT were similar with respect to blood glucose, dietary intakes and body weight changes on a given diet. Diabetic hyperfiltration occurred in WT, but was blunted in A<sub>1</sub>R–/–. A reciprocal relationship between GFR and dietary salt was found in WT diabetics, but not A<sub>1</sub>R–/– diabetics or nondiabetics of either strain. Conclusion: A<sub>1</sub>Rs determine glomerular hyperfiltration and the salt paradox in early diabetes, which is consistent with the tubulocentric principle.

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          Most cited references22

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          Predicting diabetic nephropathy in insulin-dependent patients.

          We studied whether microalbuminuria (urinary albumin excretion rates of 15 to 150 micrograms per minute) would predict the development of increased proteinuria in Type I diabetes. We also studied the influence of glomerular filtration rate, renal blood flow, and blood pressure on the later development of proteinuria. Forty-four patients who had had Type I diabetes for at least seven years and who had albumin excretion rates below 150 micrograms per minute were studied from 1969 to 1976, and 43 were restudied in 1983. Of the 14 who initially had albumin excretion rates at or above 15 micrograms per minute, 12 had clinically detectable proteinuria (over 500 mg of protein per 24 hours) or an albumin excretion rate above 150 micrograms per minute at the later examination. Of the 29 who initially had albumin excretion rates below 15 micrograms per minute, none had clinically detectable proteinuria at the later examination, although four had microalbuminuria. Those whose condition progressed to clinically overt proteinuria had elevated glomerular filtration rates and higher blood pressures at the initial examination than did those in whom proteinuria did not develop. Renal blood flow was not elevated in these patients. We conclude that microalbuminuria predicts the development of diabetic nephropathy and that elevated glomerular filtration rates and increased blood pressure may also contribute to this progression.
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            Adenosine and kidney function.

            In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.
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              Stepwise increase in arterial stiffness corresponding with the stages of chronic kidney disease.

              Patients with end-stage renal disease on maintenance dialysis therapy have a high prevalence of cardiovascular risk factors and cardiovascular disease (CVD). A similar finding is noted in patients with chronic kidney disease (CKD). The important contributors are premature and accelerated atherosclerosis and vascular calcification. We assessed the severity of arterial stiffness in 102 patients with CKD by using pulse wave velocity (PWV) and sought to identify associated risk factors. PWV was measured by calculating the distance traveled by the flow wave and divided by the time delay. Correlations between PWV and traditional cardiovascular risk factors, estimated glomerular filtration rate (GFR) per 1.73 m2 , blood pressure (BP), and pulse pressure (PP) were analyzed. PWV values in patients with CKD stages 1 to 2 and the age-matched control group were similar. There was a significant trend for a stepwise increase in PWV corresponding to advance in CKD stage (P < 0.0001). Univariate linear regression analysis showed that age, prior CVD, diabetes, hypertension, any high risk, estimated GFR per 1.73 m2 , systolic BP, and PP correlated with PWV. In the multivariate model, decreased estimated GFR per 1.73 m2 and increased systolic BP were independently associated with increased PWV in patients with CKD (model R 2 = 0.539; P < 0.0001). This is the first study to show a greater PWV in patients with more advanced CKD from stages 1 to 5. Estimated GFR per 1.73 m2 and systolic BP were the major clinical determinants of arterial stiffness in patients with CKD independent of conventional risk factors for CVD.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2009
                March 2009
                10 March 2009
                : 111
                : 3
                : p30-p38
                Affiliations
                Departments of aMedicine and bPharmacology, University of California San Diego, and cVA San Diego Healthcare System, San Diego, Calif., USA
                Article
                208211 PMC2904473 Nephron Physiol 2009;111:p30
                10.1159/000208211
                PMC2904473
                19276628
                bdb3547f-ec2e-4521-9841-3a26f75a51eb
                © 2009 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
                : 20 August 2008
                : 01 December 2008
                Page count
                Figures: 3, Tables: 1, References: 39, Pages: 1
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Diabetes,Tubuloglomerular feedback,Salt paradox,Tubular hypothesis,Diabetic nephropathy,Glomerular hyperfiltration,Proximal tubule,Adenosine A1 receptor

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