Norcantharidin Ameliorates Proteinuria, Associated Tubulointerstitial Inflammation and Fibrosis in Protein Overload Nephropathy

Liu, Fu You; Liu, Ying; Peng, You; Ye, Kun; Li, Jun; Liu, Ying‐Hong; Duan, Shao‐Bin; Ling, Guanghui; Xu, Xin; Zhou, Letian

doi:10.1159/000112850

Cited by 29 publications

(30 citation statements)

References 61 publications

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“…However, the nephrotoxicity associated with NCTD treatment is absent. 4 It has been confirmed in our previous studies that NCTD was capable of attenuating renal interstitial fibrosis in rat models with protein overload nephropathy, 5 obstructive nephropathy (data not shown), and DN. 6 Based on in vitro studies, we found that NCTD could block the transforming growth factor-b1 (TGF-b1)-mediated renal tubular epithelial cell transdifferentiation (data not shown).…”

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confidence: 56%

“…Mitochondrialdependent caspase activation cascade induced by NCTD is also thought to be responsible for the regulation of cell Antifibrotic effect of NCTD and CaN pathway Y Li et al apoptosis. 16,17 In our previous study, we reported that NCTD attenuated renal interstitial fibrosis in rat models with protein overload nephropathy, 5 obstructive nephropathy (data not shown), and DN. 6 Furthermore, we demonstrated the in vitro inhibition by NCTD of phosphorylation of Smad2/Smad3 induced by TGF-b and blockade of TGF/Smad pathway-mediated epithelialÀmesenchymal transition (EMT) in HK-2 cells (data not shown).…”

Section: Effects Of Nctd On Can/nfatc Signaling Pathway In Hk-2 Cellsmentioning

confidence: 88%

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Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

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confidence: 56%

Section: Effects Of Nctd On Can/nfatc Signaling Pathway In Hk-2 Cellsmentioning

confidence: 88%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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“…Norcantharidin (NCTD) is a synthetic derivative of cantharidin. Our previous studies first reported that NCTD could reduce renal interstitial fibrosis in the rat models of protein overload nephropathy 4 and obstructive nephropathy (data not shown). In in vitro studies, we found that NCTD could block the TGF-b1-mediated renal tubular epithelial cells' transdifferentiation.…”

Section: Introductionmentioning

confidence: 93%

“…Body weight was measured once a week. Rats with DN were randomly divided into three groups that were either untreated or treated with low-dose NCTD (0.05 mg/kg/day) or high-dose NCTD (0.1 mg/kg/day) 4 (n = 12 in each group). An additional set of rats fed with normal diet and given the same dose of intraperitoneal injection of citrate buffer was served as the control group (n = 8).…”

Section: Experimental Dn Modelmentioning

confidence: 99%

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Chen

Liu

et al. 2011

Renal Failure

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Objective: To investigate the effects of norcantharidin (NCTD) on tubulointerstitial fibrosis of diabetic nephropathy (DN) in streptozotocin-induced rat model. Methods: Sprague-Dawley rats were randomly divided into control group, model group, low-dose NCTD (0.05 mg/kg/day) group, and high-dose NCTD (0.1 mg/kg/day) group. The model group was induced by injection intraperitoneally with 30 mg/kg streptozotocin in 0.1 mol/L sodium citrate solution (pH 4.5), after high-calorie foods were given for 2 months. NCTD was administered daily after the DN rat model was built. Rats were sacrificed at the end of the third and the eighth week; renal fibrosis and the expression of FN, collagen IV, TGF-b1, and calcineurin (CaN) were detected by Masson and immunohistochemistry staining, respectively. Results: Tubulointerstitial fibrosis was observed in DN rats, this kind of pathological changes was ameliorated in NCTD treatment group (p < 0.05). The expressions of FN, collagen IV, and TGF-b1 protein increased in the tubulointerstitial field of DN rats compared with the rats in control group. NCTD treatment could dose-dependently decrease their expression and reverse the fibrotic degree (p < 0.05). Meanwhile, the expression of CaN was detected in tubular fields of normal kidney and increased in the tubulointerstitial field in DN rats. However, NCTD downregulated its expression in a dosedependent manner (p < 0.05). Conclusions: NCTD could downregulate FN, collagen IV, and TGF-b1 expression in tubulointerstitial fields and attenuate tubulointerstitial fibrosis in the early stage of DN rats. NCTD also alleviated the expression of CaN in tubules in DN. The relationship between the role of NCTD's anti-tubulointerstitial fibrosis and its inhibition to CaN expression remains to be further elucidated.

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“…In addition, it may participate in the progression of TID as an independent etiological factor. 3,15 TID is the pathological process common to all chronic renal diseases developing to ESRD, and the prognosis of kidney disease is determined by the degree of TID. 16 Therefore, searching for clinical factors associated with TID induced by proteinuria is of great significance for the determination of the development and prognosis of kidney disease.…”

Section: Discussionmentioning

confidence: 99%

The relationship between the TGF-β1 gene −509C/T polymorphism and tubulointerstitial damage resulting from primary nephrotic syndrome

et al. 2010

Renal Failure

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Background: The aim of this study was to investigate the correlation between the transforming growth factor (TGF)-b1 gene −509C/T polymorphism and the susceptibility to primary nephrotic syndrome (PNS), and in particular to the severe degree of tubulointerstitial damage (TID) seen in Chinese. Methods: Ninety-eight PNS patients and 128 normal controls were studied. The extent of tubulointerstitial changes was evaluated and patients were divided into two groups according to the severe or mild degree of TID. The TGF-b1gene −509C/ T polymorphism was detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and the serum level of TGF-b1 was determined by enzyme-linked immunosorbent assay (ELISA). Results: No statistical differences in genotype or allele frequency of the TGF-b1 gene −509C/T were found between PNS and normal subjects. However, T allele and CT + TT genotype frequency were higher in the PNS with severe TID than the mild TID and controls. Additionally, the serum concentration of TGF-b1 was significantly higher in the PNS with severe TID group than the other two groups and in the TT genotype individuals than the CC and CT genotype individuals. A logistic regression analysis demonstrated that TGF-b1 gene −509C/T genotype was the risk factor of TID in PNS patients [OR (odd ratio) 2.34, confidence interval (CI) 0.98-3.46, p = 0.012]. Conclusion. TGF-b1 gene −509C/T polymorphism was associated with severe TID. The higher value in serum concentration of TGF-b1 was also associated with severe TID and the TT genotype/T allele. T allele gene might be the important risk factor for susceptibility.

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Norcantharidin Ameliorates Proteinuria, Associated Tubulointerstitial Inflammation and Fibrosis in Protein Overload Nephropathy

Cited by 29 publications

References 61 publications

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

The relationship between the TGF-β1 gene −509C/T polymorphism and tubulointerstitial damage resulting from primary nephrotic syndrome

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