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

Tsujimura, Tsuyoshi; Nagamine, Jun; Sugaru, Eiji; Nakagawa, Tsutomu; Ono-Kishino, Michiko; Tokunaga, Teruhisa; Kitoh, Makoto; Nagata, Ryu; Taiji, Mutsuo

doi:10.1159/000167795

Cited by 4 publications

(5 citation statements)

References 44 publications

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“…The 5/6 Nx rat model is a well-established model of chronic kidney disease [19]. In agreement with this, we observed significant renal dysfunction in our 5/6 Nx rats, as indicated by increased urine albumin secretion, serum BUN and Scr levels.…”

Section: Discussionsupporting

confidence: 90%

Netrin-1 Attenuates the Progression of Renal Dysfunction by Inhibiting Peritubular Capillary Loss and Hypoxia in 5/6 Nephrectomized Rats

Cao

Feng²,

Bai³

et al. 2012

Kidney Blood Press Res

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Background/Aims: The aim of this study was to investigate the effect of netrin-1 on peritubular capillary (PTC) loss and hypoxia in 5/6 nephrectomized (Nx) rats. Methods: Male Sprague-Dawley rats were divided into three groups (n = 10 rats/group): sham-operated rats treated with control adenovirus; 5/6 Nx rats treated with control adenovirus; and 5/6 Nx rats treated with recombinant adenovirus mediated netrin-1 gene (Ad-netrin-1) therapy. Rats were killed 12 weeks after surgery. Blood urea nitrogen (BUN), serum creatinine (Scr) and 24-h urinary albumin excretion rates were measured. Pathological changes in renal tissues were analyzed histologically. The concentration of netrin-1, CD34, and hypoxia-inducible factor-1α (HIF-1α) were analyzed by immunohistochemistry, Western blotting and real-time PCR. Results: Renal function and histopathological damage were significantly improved in Adnetrin-1 treated 5/6 Nx rats, compared with rats treated with the control adenovirus in the 5/6 Nx group. Furthermore, Ad-netrin-1 treatment induced a significant increase in renal PTC density, accompanied by a significant decrease in HIF-1α expression. Conclusion: Adenovirus mediated netrin-1 treatment attenuates PTC damage, relieves tissues hypoxia and improves renal function, thus alleviating renal pathological changes and interstitial fibrosis in 5/6 Nx rats.

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Section: Discussionsupporting

confidence: 90%

Netrin-1 Attenuates the Progression of Renal Dysfunction by Inhibiting Peritubular Capillary Loss and Hypoxia in 5/6 Nephrectomized Rats

Cao

Feng²,

Bai³

et al. 2012

Kidney Blood Press Res

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“…20) In addition, it was also reported that single treatment with lisinopril significantly suppresses the progression of CKD in remnant kidney rats. 28) Because treatment with high dose of lisinopril or SMP-534 completely inhibits renal progression in 5/6Nx rats, we used suboptimal dose of SMP-534 and lisinopril to evaluate the combined effect of these agents.…”

Section: Discussionmentioning

confidence: 97%

“…[18][19][20] Accordingly, we have previously shown that combination therapy with SMP-534 and ARB, losartan, is effective in the treatment of diabetic nephropathy in diabetic db/db mouse. 21,22) However, we have not examined the effect of combination therapy with ACEI and SMP-534 on CKD models.…”

Section: )mentioning

confidence: 99%

“…18,19) Unlike ARB and ACEI, which exhibit renoprotective effects via reduction of intraglomerular pressure, [7][8][9] the renoprotective effect of SMP-534 is via a non-antihypertensive mechanism. [18][19][20] Accordingly, we have previously shown that combination therapy with SMP-534 and ARB, losartan, is effective in the treatment of diabetic nephropathy in diabetic db/db mouse. 21,22) However, we have not examined the effect of combination therapy with ACEI and SMP-534 on CKD models.…”

mentioning

confidence: 99%

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Combination Therapy with SMP-534 and an Angiotensin-Converting Enzyme Inhibitor Provides Additional Renoprotection in 5/6 Nephrectomized Rats

Tsujimura¹,

Nagamine²,

Sugaru³

et al. 2009

Biological & Pharmaceutical Bulletin

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Chronic kidney disease (CKD) is a common health problem that can progress to end-stage renal disease (ESRD). ESRD has dramatically increased worldwide, 1) however, therapeutic strategies that suppress the progression of CKD to ESRD are still limited.Angiotensin II, the main product of the rennin-angiotensin system, is deeply involved in the pathogenesis of CKD.2) In fact, angiotensin II contributes to glomerular capillary hypertension and has direct effects on mesangial cells and the glomerular filtration barrier.3,4) Because glomerular capillary hypertension is known to cause or aggravate renal damage, systemic and glomerular pressures must be controlled by antihypertensive agents, such as angiotensin-converting enzyme inhibitors (ACEI) or angiotensin-receptor blocker (ARB), to suppress the progression of CKD. 5,6) In fact, many studies have demonstrated the efficacy of ARB or ACEI in CKD models.7-9) Although ARB and ACEI are now the first choice of therapeutic agents for the treatment of CKD, some clinical studies have demonstrated that these agents can only delay ESRD onset but cannot completely prevent it. 6,10) Therefore, it is necessary to develop new drugs to avoid progression to ESRD.Pathological accumulation of extracellular matrix (ECM) in the glomeruli is one of the characteristics of CKD. 11,12) Experimental results have demonstrated that accumulation of ECM is mediated via the transforming growth factor-b (TGF-b).13) TGF-b promotes accumulation of ECM by increasing the expression of ECM genes, such as collagen and proteoglycan, and inhibiting the expression of ECM-degrading enzymes such as collagenase.14) Because accumulation of ECM is inhibited by anti-TGF-b antibodies in diabetic db/db mouse, 15,16) it is believed that inhibition of TGF-b signal cascade is a good strategy for suppressing the progression of CKD. 17)We have previously reported that SMP-534, a low molecular-weight inhibitor of TGF-b-induced ECM production, inhibits TGF-b-stimulated production of ECM in fibroblasts and shows renoprotection effects in both diabetic db/db mouse and remnant kidney rats.18,19) Unlike ARB and ACEI, which exhibit renoprotective effects via reduction of intraglomerular pressure, 7-9) the renoprotective effect of SMP-534 is via a non-antihypertensive mechanism. [18][19][20] Accordingly, we have previously shown that combination therapy with SMP-534 and ARB, losartan, is effective in the treatment of diabetic nephropathy in diabetic db/db mouse. 21,22) However, we have not examined the effect of combination therapy with ACEI and SMP-534 on CKD models. Many clinical studies reported that treatment with ACEI has beneficial effects on the patients with CKD. 23,24) For example, Ramipril Efficacy In Nephropathy (REIN) study demonstrated that treatment with ramipril reduces ESRD risk about close to 50% in the patients with CKD. 23,24) Moreover, daily drug cost of ACEI, which have been already sold as generic drugs, is cheaper than that of ARB. 25) Therefore, 2007 the National Kidney Foundation Kidney Disease Outcome...

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“…Additionally, we have studied whether SMP-534 has beneficial effects on renal fibrosis. We have shown that treatment with SMP-534 inhibits accumulation of ECM in kidney of diabetic db/db mouse or 5/6 nephrectomized rats and ameliorates renal function (13,15). In the present study, we investigated whether SMP-534 has beneficial effects on pulmonary fibrosis in bleomycin-treated hamsters.…”

mentioning

confidence: 89%

The anti-fibrotic agent SMP-534 attenuates bleomycin-induced pulmonary fibrosis in hamsters

Tsujimura¹,

Ono-Kishino²,

Nagamine³

et al. 2009

Biomed. Res.

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Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of ECM and loss of pulmonary function. However, no cure exists for this disease, and current treatments often fail to slow its progression or relieve its symptoms. We have previously reported that the anti-fibrotic agent SMP-534 has beneficial effects on renal fibrosis in animal model of nephropathy. In this study, we examined whether SMP-534 has beneficial effects on pulmonary fibrosis in bleomycin-treated hamsters. Treatment with SMP-534 [low dose (70 mg/kg) or high dose (110 mg/kg)] counteracted inhibition of body weight increase induced by bleomycin. In addition, SMP-534 significantly inhibited bleomycin-induced increase in lung hydroxyproline level, an index of collagen formation. Moreover, SMP-534 significantly ameliorated histological pulmonary fibrotic changes induced by bleomycin. The results of this study indicate that the anti-fibrotic agent SMP-534 may offer a new therapeutic option for the treatment of pulmonary fibrosis.

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

Cited by 4 publications

References 44 publications

Netrin-1 Attenuates the Progression of Renal Dysfunction by Inhibiting Peritubular Capillary Loss and Hypoxia in 5/6 Nephrectomized Rats

Netrin-1 Attenuates the Progression of Renal Dysfunction by Inhibiting Peritubular Capillary Loss and Hypoxia in 5/6 Nephrectomized Rats

Combination Therapy with SMP-534 and an Angiotensin-Converting Enzyme Inhibitor Provides Additional Renoprotection in 5/6 Nephrectomized Rats

The anti-fibrotic agent SMP-534 attenuates bleomycin-induced pulmonary fibrosis in hamsters

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