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Niao Du Kang Mixture Increases the Expression of mir-129-5p to Relieve Renal Fibrosis.

ABSTRACT: Objective:To investigate the efficacy of Niao Du Kang (NDK) mixture in renal fibrosis of rats and to explore the mechanism underlying the effect of NDK on renal fibrosis. Methods:Unilateral ureteral obstruction (UUO) was used to replicate a rat renal interstitial fibrosis model. The drug-administered groups were given 20?ml/kg (NDK-H), 10?ml/kg (NDK-M), and 5?ml/kg (NDK-L) NDK mixture once a day for 21 days beginning 48 hours after surgery. The 24-hour urine protein and serum creatinine (CR) levels in the sham group rats, UUO rats, and NDK mixture-treated rats were measured after the last administration. The pathological changes of rat kidney tissue were observed by HE staining. The degree of fibrosis was observed by Masson's staining and scored. The expression levels of TGF-?, ?-SMA mRNA, and mir-129-5p in kidney were detected by qRT-PCR. HK-2 cells were treated with 5?ng/ml TGF-? to induce HK-2 cell fibrosis. The expression levels of TGF-?, ?-SMA mRNA, and mir-129-5p in HK-2?cells were detected by qRT-PCR. TargetScan predicted the target gene of mir-129-5p, HK-2 cells were transfected with mir-129-5p mimic, and an overexpressed mir-129-5p HK-2?cell model was constructed. qRT-PCR was used to detect the expression of PDPK1 mRNA. Western blot was used to detect the expression of PDPK1, AKT, and p-AKT in HK-2?cells induced by TGF-? and in UUO rats. Results:NDK mixture significantly reduced the 24-hour urine protein and CR levels of UUO rats. HE staining showed that the NDK mixture group exhibited a significantly reduced degree of renal interstitial fibrosis. NDK mixture also reduced the expression of TGF-? and ?-SMA, and the middle-dose group showed a better therapeutic effect. In vitro studies showed that NDK mixture-containing serum increased the expression of mir-129-5p to reduce renal fibrosis. In addition, NDK mixture increased the expression of mir-129-5p in vivo. Further studies indicated that mir-129-5p could target PDPKl to reduce its expression. The NDK-containing serum group also exhibited reduced expression of PDPK1. Conclusion:NDK mixture can significantly improve renal function and improve renal fibrosis in UUO model rats. Furthermore, NDK mixture can inhibit the expression of PDPK1 by upregulating the expression of mir-129-5p and then inhibiting the PI3K/AKT pathway to improve renal fibrosis.

SUBMITTER: Li YL

PROVIDER: S-EPMC7222611 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Niao Du Kang Mixture Increases the Expression of mir-129-5p to Relieve Renal Fibrosis.

Li Yan-Lin YL Liu Lin-Na LN Huang Lin L An Hai-Wen HW Jian Jian-Lin JL Pang Jie J Lin Fen-Na FN Yang Wen-Qin WQ Li Jin-Shan JS Jiang Qian Q Wang Hong H

Evidence-based complementary and alternative medicine : eCAM 20200504

<h4>Objective</h4>To investigate the efficacy of Niao Du Kang (NDK) mixture in renal fibrosis of rats and to explore the mechanism underlying the effect of NDK on renal fibrosis.<h4>Methods</h4>Unilateral ureteral obstruction (UUO) was used to replicate a rat renal interstitial fibrosis model. The drug-administered groups were given 20 ml/kg (NDK-H), 10 ml/kg (NDK-M), and 5 ml/kg (NDK-L) NDK mixture once a day for 21 days beginning 48 hours after surgery. The 24-hour urine protein and serum crea ...[more]

PMID: 32454849

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Project description:MethodsQuantification of 24-hour urine protein (24 h-Upro) and serum creatinine (Scr) levels was performed. The protein and mRNA expression levels of E-cadherin, α-SMA, collagen I, β-catenin, Wnt-1, and LEF-1 in peritoneal tissue were measured. In addition, the pathological morphology and ultrastructure of peritoneum were observed.ResultsAfter 5/6 nephrectomy + high glucose peritoneal dialysate + lipopolysaccharide (LPS) treatment, the Scr and 24 h-Upro of rats increased compared with normal rats, and the peritoneal tissue was damaged and thickened, showing fibrotic changes. Compared with the model group, the Scr and 24 h-Upro levels and the levels of E-cadherin, α-SMA, Wnt-1, collagen I, and LEF-1 protein expression in each Niao Du Kang mixture dosage group decreased. The protein expression of β-catenin and the mRNA expression of E-cadherin, α-SMA, Wnt-1, collagen I, β-catenin, and LEF-1 decreased in the high and medium Niao Du Kang mixture dose groups. Hematoxylin and eosin staining showed that the peritoneum of the rats was not only thicker in the model group than in the sham operation group (P < 0.01) but also accompanied by apparent inflammatory cell infiltration, tissue edema, and fibrosis. Compared with the model group, all the Niao Du Kang mixture groups demonstrated various degrees of mitigation in peritoneal thickness and fibrosis (P < 0.01). The strongest effect was observed in the medium-dose group. Transmission electron microscopy showed that the degree of injury of the peritoneal mesothelial cells was ranked as follows: model group > positive drug group > Niao Du Kang mixture high-dose group.ConclusionsThe Niao Du Kang mixture may effectively decrease the peritoneal thickness and fibrosis degree through its effect on the Wnt/β-catenin signaling pathway involved in EMT. The present study provides data that assist in elucidating the potential function of the Niao Du Kang mixture in treating or preventing PF.

Project description:Osteoporosis is a frequently occurring bone disease in middle-aged and aged men and women. However, current therapies on this disease are still not ideal. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNA with a length of 18-25 nucleotides. miRNAs have been identified as important regulators for development, metabolism, carcinogenesis, and bone formation. miR-129-5p has been reported as a regulator of cancer and neuroscience, whereas studies about its function on bone formation is still limited. In this study, we investigated the function and mechanism of miR-129-5p on osteoblast differentiation and bone formation. We have assessed the expression of miRNAs in bone mesenchymal stem cells from aging and menopause osteoporosis C57BL6 mice. The expression of miR-129-5p was altered in all osteoporosis models. Besides, the expression of miR-129-5p was negatively correlated with osteoblastic differentiation markers in the femur tissues of C57BL/6 mice of different ages. We further demonstrated that overexpression of miR-129-5p inhibited osteoblast differentiation in MC3T3-E1 cell line, as well as bone formation of C57BL/6 mice. On the other hand, down-regulation of miR-129-5p enhanced osteoblast differentiation and bone formation. We also found that miR-129-5p inhibited Wnt/β-catenin pathway in osteoblast. The target gene of miR-129-5p has been forecasted and proved as Tcf4. We further found that plasmid containing Tcf4-3' UTR sequence enhanced osteoblast differentiation, as well as Wnt/β-catenin pathway in MC3T3-E1 cells. To further investigate the rescue effect of miR-129-5p inhibitor, we manufactured bioengineered novel recombinant miR-129-5p inhibitor through Escherichia coli system and then tested its function. The results showed that the novel recombinant miR-129-5p inhibitor promoted osteoblast differentiation and greatly ameliorated menopause osteoporosis in C57BL6 mice. In conclusion, we have discovered miR-129-5p as an inhibitor of bone formation. miR-129-5p inhibited downstream transcription factors of Wnt/β-catenin pathway through targeting Tcf4. Moreover, novel recombinant miR-129-5p inhibitor showed rescue effect on osteoporosis. This study has revealed a new mechanism of osteogenic differentiation and provided novel therapeutic strategies for treatment of skeletal disorders.

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Dataset Information

Niao Du Kang Mixture Increases the Expression of mir-129-5p to Relieve Renal Fibrosis.

Publications

Niao Du Kang Mixture Increases the Expression of mir-129-5p to Relieve Renal Fibrosis.

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