Curcumin attenuates diabetic nephropathy by inhibiting PKC‐α and PKC‐β<sub>1</sub> activity in streptozotocin‐induced type I diabetic rats

Soetikno, Vivian; Watanabe, Kenichi; Sari, Flori R.; Harima, Meilei; Thandavarayan, Rajarajan Amirthalingam; Veeraveedu, Punniyakoti T.; Arozal, Wawaimuli; Sukumaran, Vijayakumar; Lakshmanan, Arun Prasath; Arumugam, Somasundaram; Suzuki, Kenji

doi:10.1002/mnfr.201100080

Cited by 120 publications

(83 citation statements)

References 55 publications

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“…35 Meanwhile, mice harboring two point mutations in the Mll2 gene, which encodes one of the H3K4 methyltransferases, exhibit spontaneous insulin resistance. 36 Of interest, Soetikno et al 37 have shown that curcumin, a nonspecific p300 inhibitor, alleviates diabetic nephropathy in STZ-injected rats. Our data allude to a scenario where high glucose engages p300 and WDR5 in collagen activation and tubulointerstitial fibrosis and reinforce the notion that screening for small molecule compounds that can inhibit the activities of these proteins may yield novel therapeutic solutions.…”

Section: Discussionmentioning

confidence: 99%

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Xu¹,

Qin³

et al. 2015

Journal of the American Society of Nephrology

112

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Diabetic nephropathy (DN) is one of the most common complications associated with diabetes and characterized by renal microvascular injury along with accelerated synthesis of extracellular matrix proteins causing tubulointerstitial fibrosis. Production of type I collagen, the major component of extracellular matrix, is augmented during renal fibrosis after chronic exposure to hyperglycemia. However, the transcriptional modulator responsible for the epigenetic manipulation leading to induction of type I collagen genes is not clearly defined. We show here that tubulointerstitial fibrosis as a result of DN was diminished in myocardin-related transcription factor A (MRTF-A) -deficient mice. In cultured renal tubular epithelial cells and the kidneys of mice with DN, MRTF-A was induced by glucose and synergized with glucose to activate collagen transcription. Notably, MRTF-A silencing led to the disappearance of prominent histone modifications indicative of transcriptional activation, including acetylated histone H3K18/K27 and trimethylated histone H3K4. Detailed analysis revealed that MRTF-A recruited p300, a histone acetyltransferase, and WD repeat-containing protein 5 (WDR5), a key component of the histone H3K4 methyltransferase complex, to the collagen promoters and engaged these proteins in transcriptional activation. Estradiol suppressed collagen production by dampening the expression and binding activity of MRTF-A and interfering with the interaction between p300 and WDR5 in renal epithelial cells. Therefore, targeting the MRTF-A-associated epigenetic machinery might yield interventional strategies against DN-associated renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Xu¹,

Qin³

et al. 2015

Journal of the American Society of Nephrology

112

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“…However, the definite proximate regulators linking ET-1 and VEGF signaling in diabetic hearts have not yet been identified. TGF-b and CTGF are involved in extracellular matrix (ECM) accumulation both in the early and the later stages of diabetes (26). Several lines of experimental and clinical evidence support a major role for TGF-b in develop- (27,28).…”

Section: Discussionmentioning

confidence: 99%

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

Yang¹,

Li²,

Shi³

et al. 2012

Anadolu Kardiyol Derg

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Objective: To investigate the potential beneficial effect of bosentan in ameliorating fibrotic agents in diabetic mice. Methods: Male 6-week old C57BL/6 mice were divided into 3 groups (N=20): Control group, diabetes mellitus (DM) group and DM-B group (diabetes with bosentan group). Streptozotocin (STZ) was injected as 200 mg/Kg for single dose, i.p. (intraperitoneal injection). Fasting blood glucose (FBG) was measured at 0-, 1-, 2-week after STZ injection to confirm that diabetes was induced in the mice. Bosentan (100mg/Kg) and placebo was given i.g. (intragastric administration) once a day immediately after STZ injection for 18 weeks. The mRNA expression of tissue growth factor beta (TGF-b), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) and collagen-1 were evaluated by RT-PCR and real-time PCR. Differences in the data between the groups were compared by Student t-test for independent samples. Results: After 18 weeks of diabetic situation, FBG of DM-B mice was significantly higher than that of control mice and was similar with that of DM mice (DM mice vs. control mice, p<0.001; DM-B vs. control mice, p<0.001; DM mice vs. DM-B mice, p>0.05). The cardiac VEGF mRNA (a potent angiogenic factor) level in DM-B mice was significantly higher than DM mice (p<0.01). The heart of DM-B mice also showed lower expression of fibrotic genes (TGF-b, CTGF and collagen-1) than DM mice (p<0.01). Conclusion: These findings indicate the potential usefulness of an ET receptor antagonist bosentan in the amelioration of fibrotic agents, which may promote tissue fibrosis. This may provide a promising therapeutical strategy for diabetic cardiac fibrosis.

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“…Four days after the STZ injection, blood sugar was assessed in overnight-fasted rats using a glucometer (SD Biosensor India, New Delhi, India) and 80 % of rats were found to have developed diabetes; rats with blood glucose levels >17 mmol/L were considered diabetic. 35 These rats were maintained in the diabetic condition for 40 days, with a 90 % survival rate, to achieve DN. Each rat was placed in a metabolic cage to collect urine for biochemical analysis and rats with proteinuria were randomly divided into a DN control group (Group 2) and a PTY-2-treated group (Group 3; n = 6 rats in each group).…”

Section: Experimental Protocol and Induction Of Dnmentioning

confidence: 99%

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase‐9 expression in the kidney of diabetic rats

Tripathi

Shukla

Pandey

et al. 2016

Journal of Diabetes

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Background: Currently, no drug is available to directly target the signaling molecules involved in the pathogenesis of diabetic nephropathy (DN); only antihypertensive and antidiabetic drugs are in clinical use. In the present study, the therapeutic effects of a active fraction of tubers from Pueraria tuberosa (hereafter referred to as PTY-2) were investigated in streptozotocin (STZ)-diabetic rats with DN, with particular emphasis on its effects on extracellular matrix (ECM) accumulation and matrix metalloproteinase (Mmp)-9 expression in kidney tissue. Methods: Rats were injected with 55 mg/kg, i.p., STZ. After 40 days, rats were divided into groups as follows (n = 6 per group): Group 1, age-matched rats not injected with STZ (non-diabetic control); Group 2, STZ-diabetic DN rats; and Group 3, PTY-2 (30 mg/100 g, p.o.)-treated DN rats. After 20 days treatment, the effects of PTY-2 on serum urea and creatinine concentrations, urinary levels of glucose, creatinine, protein, and ketone bodies, and urine pH were determined. Kidney tissue was evaluated for Mmp-9 expression and histological changes. Results: Blood glucose, serum urea, creatinine, and urine protein levels were significantly higher, and creatinine clearance was significantly lower, in Group 2 versus Group 1 rats. There was a higher degree of glomerulosclerosis, expansion of the mesangial matrix, and excess ECM deposition and eosinophilic casts in kidneys from Group 2 versus Group 1 rats. Furthermore, Mmp-9 activity and expression were significantly reduced in kidney homogenate of Group 2 versus Group 1 rats. Interestingly, PTY-2 treatment significantly reversed all these changes in DN rats. Conclusion: Treatment of DN rats with PTY-2 significantly attenuated the severity of DN by increasing the expression and activity of Mmp-9, consequently degrading the ECM accumulated in kidney tissue.

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Curcumin attenuates diabetic nephropathy by inhibiting PKC‐α and PKC‐β₁ activity in streptozotocin‐induced type I diabetic rats

Abstract: These results prove that curcumin produces dual blockade of both PKC-α and PKC-β1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.

Cited by 120 publications

References 55 publications

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase‐9 expression in the kidney of diabetic rats

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Curcumin attenuates diabetic nephropathy by inhibiting PKC‐α and PKC‐β1 activity in streptozotocin‐induced type I diabetic rats

Abstract: These results prove that curcumin produces dual blockade of both PKC-α and PKC-β1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.

Cited by 120 publications

References 55 publications

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase‐9 expression in the kidney of diabetic rats

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Curcumin attenuates diabetic nephropathy by inhibiting PKC‐α and PKC‐β₁ activity in streptozotocin‐induced type I diabetic rats