Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease

Kurogi, Yasuhisa

doi:10.1002/med.10028

Cited by 74 publications

(40 citation statements)

References 50 publications

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“…Moreover, collagen IV and fibronectin, which are the major components of ECM, and MMP and TIMP expressions were all altered in diabetic and other nephropathies [24,25,26,27,28,29]. Expansion of ECM in tubulointerstitium and glomerulus is the typical pathological feature of diabetes [30, 31].…”

Section: Discussionmentioning

confidence: 99%

Doxycycline: A Pilot Study to Reduce Diabetic Proteinuria

Naini

Harandi²,

Bastani³

et al. 2007

Am J Nephrol

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Background: Activity of matrix metalloproteinases (MMPs), the enzymes primarily responsible for the deposition of extracellular matrix proteins, contributes to the pathogenesis of diabetic proteinuria. We evaluated the effect of doxycycline, a potent nonselective MMPs inhibitor, on reduction of proteinuria in diabetic patients. Material and Methods: In a self-control clinical trial, 35 patients with overt diabetic nephropathy (proteinuria >300 mg/24 h) received oral doxycycline 100 mg/day for 2 months. Twenty-four-hour urine volume, Cr and protein excretion were measured at baseline, after 1 and 2 months of treatment, and after 4 months of its discontinuation. Treatment-related side effects were closely monitored and documented. Results: Mean (±SD) 24-hour urine protein was 888 ± 419 mg at baseline, 884 ± 368 mg after 1 month, and 643 ± 386 mg after the 2 months of doxycycline treatment. There was statistically significant reduction in proteinuria at 2 months of treatment vs. at the baseline (p < 0.001). Mean 24-hour urine protein excretion increased to 1,021 ± 422 mg 4 months after doxycycline was discontinued. The changes in serum sodium, potassium, BUN and Cr concentrations, and blood pressure measurements during the 2 months of treatment and follow-up period were not statistically significant. Conclusion: Proteinuria in patients with diabetic nephropathy can be reduced with low dose doxycycline therapy over a 2-month period of drug administration. Further studies are necessary to determine the long-term effect, the optimal dose, and the optimal duration of this potentially novel therapy.

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Section: Discussionmentioning

confidence: 99%

Doxycycline: A Pilot Study to Reduce Diabetic Proteinuria

Naini

Harandi²,

Bastani³

et al. 2007

Am J Nephrol

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“…Following the onset of hypertension, an augmented intrarenal A-II production stimulates an exaggerated synthesis of cytokines and growth factors and a consequent increase in cell proliferation, apoptosis, and deposition of extracellular matrix [5, 6]. All of these are indicative of renal inflammatory diseases, including hypertensive and diabetic nephropathies which eventually culminate in end-stage renal failure [19, 20]. Inhibition of A-II synthesis by ACE inhibitors or downregulation of A-II cellular uptake by blockade of AT-1 receptors not only reduces systemic hypertension and intraglomerular pressure, but also slows down the course of the renal functional deterioration [7].…”

Section: Discussionmentioning

confidence: 99%

PPAR-γ Activation Inhibits Angiotensin II Synthesis, Apoptosis, and Proliferation of Mesangial Cells from Spontaneously Hypertensive Rats

Efrati

Berman²,

Ilgiyeav³

et al. 2007

Nephron Exp Nephrol

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Background/Aim: The angiotensin II level is elevated in subjects genetically prone to develop hypertension, triggering renal hypercellularity, cytokine production, and matrix deposition. Angiotensin-converting enzyme inhibition and/or angiotensin II type 1 receptor blockade attenuate renal damage. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist possessing antihypertensive and anti-inflammatory properties, was demonstrated to provide better renal protection than angiotensin-converting enzyme inhibitors. We studied the effects of in vivo peroxisome proliferator-activated receptor gamma activation by rosiglitazone on angiotensin II synthesis, proliferation, and apoptosis of mesangial cells of spontaneously hypertensive rats versus normotensive Sprague-Dawley rats. Methods: The animals consumed either a high-sodium diet (8% Na) or a normal-sodium diet (0.5% Na). Half of each group received rosiglitazone at 5 mg/kg/day. After 3 weeks, all rats were sacrificed and the mesangial cells isolated and cultured. Angiotensin II was assessed by radioimmunoassay, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and cell proliferation by [³H]thymidine incorporation. Results: Only the spontaneously hypertensive rats which consumed the high-sodium diet developed hypertension (185 ± 6 mm Hg vs. basal 128 ± 5 mm Hg; p = 0.0007) which was attenuated by rosiglitazone (to 126 ± 4 mm Hg; p = 0.34). Angiotensin II synthesis, proliferation, and apoptosis were exaggerated in mesangial cell cultures from Sprague-Dawley rats and, more so, spontaneously hypertensive rats fed the high-sodium diet, but were inhibited in cultures from rosiglitazone-treated animals. Conclusions: Peroxisome proliferator-activated receptor gamma activation, in addition to lowering blood pressure, suppresses angiotensin II synthesis and downregulates angiotensin-II-mediated proliferation and apoptosis of mesangial cells. In the context of hypertension-induced renal damage, this would mean that the renoprotective role of rosiglitazone extends beyond glycemic and lipidemic control.

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“…Glomerulosclerosis is an eventual pathogenesis of CKD observed in ESRD, and is mainly due to accumulation of extracellular matrix (ECM) in the mesangial region [6,7,8]. Accumulation of ECM in the glomeruli is considered to be one of the causes of renal insufficiency, which is indicated by markers, such as urinary albumin excretion and decline in glomerular filtration rate.…”

Section: Introductionmentioning

confidence: 99%

Chronic Administration of SMP-534 Ameliorates Renal Dysfunction in 5/6 Nephrectomized Rats

Tsujimura

Nagamine²,

Sugaru³

et al. 2008

Nephron Exp Nephrol

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Background/Aims: Chronic kidney disease (CKD) is the common cause of end-stage renal disease. Antihypertensive agents are clinically used to inhibit the progression of CKD. However, these agents cannot completely prevent progression to renal failure. We have previously reported that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H- pyrrol-1-yl]prop-1en-1-yl}-N-(methylsulfonyl)benzamide (SMP-534) improves renal disease and prevents the production of extracellular matrix in vitro. Additionally, SMP-534 inhibits glomerular fibrosis and provides renoprotection in vivo. In the present study, we investigated the effect of SMP-534 on renal dysfunction in a 5/6 nephrectomized (5/6Nx) rat model. Method: Five groups of rats were studied: sham operated, 5/6Nx + vehicle, 5/6Nx + SMP-534 30 mg/kg, 5/6Nx + SMP-534 60 mg/kg and 5/6Nx + SMP-534 90 mg/kg. Treatment with SMP-534 began 13 weeks after surgery, when hypertension and renal insufficiency had developed. Serum creatinine, blood urea nitrogen levels, creatinine clearance and urinary albumin were measured at specific time points. Results: Serum creatinine and blood urea nitrogen levels were significantly reduced in SMP-534-treated groups. In addition, SMP-534 dose-dependently suppressed the increase in urinary albumin excretion observed in 5/6Nx rats. Moreover, survival rates were improved in SMP-534-treated groups. Conclusion: We have shown in this study that chronic oral administration of SMP-534 improves renal dysfunction in 5/6Nx rats. These findings indicate that SMP-534 may be a new therapeutic agent for the treatment of CKD.

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Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease

Cited by 74 publications

References 50 publications

Doxycycline: A Pilot Study to Reduce Diabetic Proteinuria

Doxycycline: A Pilot Study to Reduce Diabetic Proteinuria

PPAR-γ Activation Inhibits Angiotensin II Synthesis, Apoptosis, and Proliferation of Mesangial Cells from Spontaneously Hypertensive Rats

Chronic Administration of SMP-534 Ameliorates Renal Dysfunction in 5/6 Nephrectomized Rats

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