Effect of Ruboxistaurin on Urinary Transforming Growth Factor-β in Patients With Diabetic Nephropathy and Type 2 Diabetes

Gilbert, Richard E.; Kim, Sandra A.; Tuttle, Katherine R.; Bakris, George L.; Toto, Robert D.; McGill, Janet B.; Haney, Douglas J.; Kelly, Darren J.; Anderson, Pamela W.

doi:10.2337/dc06-2079

Cited by 50 publications

(22 citation statements)

References 22 publications

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“…Since hyperfiltration is associated with diabetic nephropathy and occurs early in the natural history of diabetes before the onset of microalbuminuria, our results may identify a potentially high-risk group that can benefit from earlier renoprotective therapies. Our findings are important from a therapeutic perspective because urine cytokines/chemokines can be influenced by renoprotective medications such as ACE inhibitors in humans [33][34][35][36][37][38]. Urine cytokines/chemokines may therefore act as future therapeutic targets for novel or existing medications and can be used by clinicians to monitor treatment failure or success.…”

Section: Discussionmentioning

confidence: 99%

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

et al. 2013

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Aims/hypothesis High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus. Methods Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFR INULIN ], n=28) or normofiltration (n=21) and healthy control individuals (n=18).Results Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA 1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165±9 vs 113±2 and 116±4 ml min, respectively, p< 0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p<0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophagederived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colonystimulating factor (p≤0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p<0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p<0.01). Conclusions/interpretation Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

et al. 2013

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“…All patients were required to be on stable therapy with either an ACE inhibitor or an ARB or both for 6 months before randomization and were required to continue that therapy during the trial. After 1 year, patients who were treated with ruboxistaurin experienced significant baseline-to-endpoint reductions in albuminuria and urinary TGF-b [34 ], and maintained the estimated glomerular filtration rate (eGFR) over 1 year. In contrast, patients on placebo did not experience a significant baseline-to-endpoint change in either albuminuria or urinary TGF-b and had a significant decrease in the eGFR.…”

Section: Effects Of Ruboxistaurin In Humans With Diabetesmentioning

confidence: 97%

Protein kinase C β inhibition: the promise for treatment of diabetic nephropathy

Anderson

McGill²

2007

Current Opinion in Nephrology &Amp; Hypertension

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“…9 As in diabetic cardiomyopathy, 6 excess matrix, hypertrophy, and apoptosis are also features of diabetic nephropathy where ruboxistaurin has been shown to attenuate histological injury, functional decline, and the expression of the profibrotic and proapoptotic growth factor, transforming growth factor (TGF)-␤. 10,11 Accordingly, in the present study, we took advantage of the recently validated model of diabetic cardiomyopathy to examine the consequences of diabetes on LV PKC-␤ activity and then to assess the effects of PKC-␤ inhibition on the functional, structural and molecular components of heart failure, focusing in particular, on diastolic disease.…”

Section: Clinical Perspective See P 137mentioning

confidence: 99%

Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy

Connelly

Kelly

Zhang

et al. 2009

Circ: Heart Failure

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110

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Background-Heart failure is a common cause of morbidity and mortality in diabetic patients that frequently manifests in the absence of impaired left ventricular systolic function. In contrast to the strong evidence base for the treatment of systolic heart failure, the treatment of heart failure with preserved left ventricular function is uncertain, and therapeutic targets beyond blockade of the renin-angiotensin-aldosterone and ␤-adrenergic systems are being sought. One such target is the ␤-isoform of protein kinase C (PKC), implicated in both the complications of diabetes and in cardiac dysfunction in the nondiabetic setting. Methods and Results-Using a hemodynamically validated rodent model of diabetic diastolic heart failure, the (mRen-2)27 transgenic rat, we sought to determine whether selective inhibition of PKC-␤ would preserve cardiac function and reduce structural injury. Diabetic rats were randomized to receive either vehicle or the PKC-␤ inhibitor, ruboxistaurin (20 mg/kg per d) and followed for 6 weeks. Compared with untreated animals, ruboxistaurin-treated diabetic rats demonstrated preserved systolic and diastolic function, as measured by the slope of preload recruitable stroke work relationship (PϽ0.05) and the slope of the end-diastolic pressure volume relationship (PϽ0.01). Collagen I deposition and cardiomyocyte hypertrophy were both reduced in diabetic animals treated with ruboxistaurin (PϽ0.01), as was phosphorylated-Smad2, an index of transforming growth factor-␤ activity (PϽ0.01 for all, versus untreated diabetic rats). Conclusions-PKC-ß inhibition attenuated diastolic dysfunction, myocyte hypertrophy, and collagen deposition and preserved cardiac contractility. PKC-␤ inhibition may represent a novel therapeutic strategy for the prevention of diabetes-associated cardiac dysfunction. (Circ Heart Fail. 2009;2:129-137.)Key Words: cardiomyopathy Ⅲ diabetes mellitus Ⅲ pharmacology T he epidemic of diabetes mellitus foreshadows a vast increase in the number of patients with cardiac complications of the disease. In contrast to the emphasis on ischemic heart disease, heart failure in diabetic subjects has been relatively neglected, even though hospitalizations for acute myocardial infarction and heart failure are similar. 1 In many such patients the etiology of heart failure will be multifactorial, arising from the "toxic triad" of coronary artery disease, hypertension, and diabetic cardiomyopathy. 2 Although the existence of the latter has been debated for some time; clinical, epidemiological, pathological, and experimental studies all point to the presence of cardiac dysfunction in diabetes that is independent of hypertension and underlying coronary artery disease 2,3 manifested by early, mostly asymptomatic diastolic dysfunction that ultimately leads to congestive heart failure in the absence of impaired systolic function. 4,5 Clinical Perspective see p 137Research into diabetic cardiomyopathy and diastolic function had been hampered by the absence of a hemodynamically validated rodent model. Mor...

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Effect of Ruboxistaurin on Urinary Transforming Growth Factor-β in Patients With Diabetic Nephropathy and Type 2 Diabetes

Cited by 50 publications

References 22 publications

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Protein kinase C β inhibition: the promise for treatment of diabetic nephropathy

Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy

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