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Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy.

ABSTRACT: BACKGROUND AND PURPOSE:The endocannabinoid (EC) system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effects of peripheral blockade of the cannabinoid CB1 receptor as an add-on treatment to ACE-inhibition in type 1 diabetic mice (DM) with established albuminuria. EXPERIMENTAL APPROACH:Renal functional parameters (albumin excretion rate, creatinine clearance), tubular injury, renal structure, both EC and CB receptor levels and markers of podocyte dysfunction, fibrosis and inflammation were studied in streptozotocin-induced DM treated for 14 weeks with vehicle, the ACE-inhibitor perindopril (2 mg·kg-1 ·day-1 ), peripherally-restricted CB1 receptor antagonist AM6545 (10 mg·kg-1 ·day-1 ) or both. Treatments began at 8 weeks after diabetes onset, when early DN is established. KEY RESULTS:CB1 receptors were overexpressed in DM and neither perindopril nor AM6545 altered this effect, while both drugs abolished diabetes-induced overexpression of angiotensin AT1 receptors. Single treatment with either AM6545 or perindopril significantly reduced progression of albuminuria, down-regulation of nephrin and podocin, inflammation and expression of markers of fibrosis. However, reversal of albuminuria was only observed in mice administered both treatments. The ability of the combination therapy to completely abolish slit diaphragm protein loss, monocyte infiltration, overexpression of inflammatory markers and favour macrophage polarization towards an M2 phenotype may explain this greater efficacy. In vitro experiments confirmed that CB1 receptor activation directly inhibits retinoic acid-induced nephrin expression in podocytes and IL-4-induced M2 polarization in macrophages. CONCLUSION AND IMPLICATIONS:Peripheral CB1 receptor blockade used as add-on treatment to ACE-inhibition reverses albuminuria, nephrin loss and inflammation in DM.

SUBMITTER: Barutta F

PROVIDER: S-EPMC6240130 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy.

Barutta F F Bellini S S Mastrocola R R Gambino R R Piscitelli F F di Marzo V V Corbetta B B Vemuri V K VK Makriyannis A A Annaratone L L Bruno G G Gruden G G

British journal of pharmacology 20181106 23

<h4>Background and purpose</h4>The endocannabinoid (EC) system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effects of peripheral blockade of the cannabinoid CB<sub>1</sub> receptor as an add-on treatment to ACE-inhibition in type 1 diabetic mice (DM) with established albuminuria.<h4>Experimental approach</h4>Renal functional parameters (albumin excretion rate, creatinine clearance), tubular injury, renal structure, both EC and CB receptor levels and ...[more]

PMID: 30184259

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Project description:Background and objectivesAlbuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits.Design, setting, participants, & measurementsThis study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements.ResultsIncreasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone.ConclusionsIncreasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Dataset Information

Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy.

Publications

Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy.

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