Recent advances in pharmacotherapy for diabetic nephropathy: Current perspectives and future directions

Balakumar, Pitchai; Arora, Mandeep Kumar; Ganti, Subrahmanya S.; Reddy, Jayarami; Singh, Manjeet

doi:10.1016/j.phrs.2009.02.002

Cited by 62 publications

(37 citation statements)

References 121 publications

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“…Current clinical treatments targeting renal fibrosis involve inhibition of the renin-angiotensin-aldosterone system. 34,35 However, they are not always effective, especially when given in the later stages of CKD. 36 Within the context of renal fibrosis, TGF-b is widely implicated in disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-214 Antagonism Protects against Renal Fibrosis

Denby

Ramdas

et al. 2014

Journal of the American Society of Nephrology

130

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Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-b signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-b blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-b signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-214 Antagonism Protects against Renal Fibrosis

Denby

Ramdas

et al. 2014

Journal of the American Society of Nephrology

130

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“…3 And, so far, there has not been an ideal drug which can reverse tubulointerstitial fibrosis and alleviate the decline of renal function in DN. Norcantharidin (NCTD) is a synthetic derivative of cantharidin.…”

Section: Introductionmentioning

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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“…1,2 However, clinical data have shown that active control of blood glucose and cholesterol levels, reduction in proteinuria by blockade of the reninangiotensin-aldosterone system, and amelioration of insulin resistance do not effectively inhibit tubulointerstitial fibrosis associated with DN. 3 To date, there are no ideal agents that can reverse tubulointerstitial fibrosis and slow the decline in renal function in DN.…”

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confidence: 99%

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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Recent advances in pharmacotherapy for diabetic nephropathy: Current perspectives and future directions

Cited by 62 publications

References 121 publications

MicroRNA-214 Antagonism Protects against Renal Fibrosis

MicroRNA-214 Antagonism Protects against Renal Fibrosis

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

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

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