September 2023
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17 Reads
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3 Citations
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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Publications (3)
February 2021
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35 Reads
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10 Citations
Toxicology and Applied Pharmacology
Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN.
March 2020
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20 Reads
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3 Citations
Biochemical and Biophysical Research Communications
Diabetic kidney disease (DKD) is considered a chronic inflammatory renal disease induced by hyperglycemia. Therefore, even meticulous control of blood glucose levels cannot prevent the progression of DKD efficiently. Management of the inflammatory response could be one of the most promising strategies for treatment. We previously validated an imidazopyridine derivative (X22) as an active compound in suppressing lipopolysaccharide-induced inflammation. However, its potential for protection against DKD has not been exanimated. In the present study, streptozotocin-induced type 1 diabetic mice were used to study the effect of X22 on DKD associated inflammation and fibrosis by Q-PCR and immunoblotting assays. The results showed that X22 significantly inhibited the production of inflammatory cytokines (IL-6, TNF-α) and fibrosis biomarkers. At the same time, kidney function was dramatically improved. To elucidate the mechanism of action of X22, we examined its effects on the NRK-52E cell line. Strikingly, X22 restored the protein level of IKB-α and blocked the nuclear translocation of P65. Collectively, the data indicate that X22 can attenuate diabetic kidney dysfunction and inflammatory injury and may represent a potential agent for the treatment of DKD. It could be a potential agent for use in the treatment of DKD.
Citations (3)
... It has been reported that specific deletion of Dclk1in macrophages has demonstrated a reduction in cardiac hypertrophy, myocardial fibrosis and atherosclerotic plaques [23,24]. An additional study has provided evidence that reducing Dclk1 in the context of diabetic cardiomyopathy through genetic knockout or inhibitors can reduce cardiac fibrosis [25]. Translating these studies to our findings would suggest that decreased Dclk1 in response to TGF-β treatment in isolated MI fibroblasts could be a mechanism to balance and modulate a pro-fibrotic response. ...
- Citing Article
September 2023
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
... SV40-MES-13 cells were obtained from Procell (Wuhan, China) and were cultured in low-glucose DMEM/F12 (3:1; v/v) containing 8% FBS (Gibco, New York, NY, USA) and 1% penicillin/streptomycin (BasalMedia, Shanghai, China) and grown at 37 • C in 5% CO 2 incubator. To stimulate fibrosis and inflammation, the cells were treated with high glucose (11 mM, 22 mM or 33 mM) for 24 h, and mannitol was used to control osmotic pressure [25,26]. Specifically, the control group cells were given 5.5 mM D-glucose plus 27.5 mM mannitol; the 11 mM high glucose group cells were given 11 mM D-glucose plus 22 mM of mannitol; the 22 mM high glucose group cells were given 22 mM D-glucose and 11 mM of mannitol; and the 33 mM high glucose group cells were given 33 mM D-glucose without mannitol. ...
- Citing Article
February 2021
Toxicology and Applied Pharmacology
... Factors such as hyperglycemia, glycation end products, and infection lead to the enhancement of oxidative stress in the body [8], activating IкB kinase (IKK), and the activated IKK phosphorylates IκB, thereby separating it from NF-κB, releasing NF-κB p50/p65, and translocating NF-kB into the nucleus, binding to target gene loci to initiate downstream gene expression, accelerating the stimulation of the expression and transcription of various signaling factors in the body, and increasing the level of inflammatory factors in the body [9]. Among the many inhibitory proteins of NF-kB, IKB-α is the most important and the first to be cloned [10], initiating the transcription and expression of a series of specific proinflammatory factor genes [11]. ...
- Citing Article
March 2020
Biochemical and Biophysical Research Communications