Visnyk Kyivs'koho natsional'noho universytetu imeni Tarasa Shevchenka. Biolohiia最新文献

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THE EFFECT OF COMPOUND DM509 ON KIDNEY FIBROSIS IN THE CONDITIONS OF THE EXPERIMENTAL MODEL. 化合物dm509在实验模型条件下对肾纤维化的影响。

Visnyk Kyivs'koho natsional'noho universytetu imeni Tarasa Shevchenka. Biolohiia Pub Date : 2020-01-01 DOI: 10.17721/1728_2748.2020.80.10-15

A Stavniichuk, O Savchuk, Abdul Hye Khan, Wojciech K Jankiewicz, John D Imig, Daniel Merk

{"title":"THE EFFECT OF COMPOUND DM509 ON KIDNEY FIBROSIS IN THE CONDITIONS OF THE EXPERIMENTAL MODEL.","authors":"A Stavniichuk, O Savchuk, Abdul Hye Khan, Wojciech K Jankiewicz, John D Imig, Daniel Merk","doi":"10.17721/1728_2748.2020.80.10-15","DOIUrl":"https://doi.org/10.17721/1728_2748.2020.80.10-15","url":null,"abstract":"Renal fibrosis is a critical event in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). Unfortunately, there are few options to target renal fibrosis in order to develop novel anti-fibrotic agents that could prevent CKD progression to ESRD. We evaluated the efficacy of a novel dual-acting molecule, DM509, in preventing renal fibrosis using the unilateral ureteral obstruction (UUO) renal fibrosis mouse model. DM509 acts simultaneously as a farnesoid X receptor agonist (FXRA) and a soluble epoxide hydrolase inhibitor (sEHi). In this study, groups of 8-12 weeks old C57BL/6J male mice went through either UUO or sham surgery (n=6/group). Mice were pre-treated with DM509 (10mg/kg/d) or vehicle administered in drinking water one day prior to the UUO surgery. Sham, vehicle and DM509 treatments continued until day 10 and blood and kidney tissue were collected for biochemical, histological, and gene expression analysis at the end of the treatment protocol. The UUO group exhibited kidney dysfunction with elevated blood urea nitrogen (BUN) compared to the sham group (63±7 vs. 34±6 mg/dL). DM509 treatment prevented renal dysfunction as evident from 36% lower BUN level in the DM509 treated UUO mice compared to UUO mice treated with vehicle. Vehicle treated UUO mice demonstrated renal fibrosis with elevated kidney hydroxyproline content (213±11 vs. 49±9 μg/mg protein) and kidney collagen positive area (13±2% vs. 1.1±0.1%) compared to the sham group. We found that DM509 treatment prevented renal fibrosis and DM509 treated mice had 34-66% lower levels of kidney hydroxyproline and collagen positive renal area compared to vehicle-treated UUO mice. In conclusion, our data provide evidence that the novel dual-acting FXRA and a sEHi, DM509, prevented renal dysfunction and renal fibrosis in UUO mouse model.","PeriodicalId":93155,"journal":{"name":"Visnyk Kyivs'koho natsional'noho universytetu imeni Tarasa Shevchenka. Biolohiia","volume":"80 1","pages":"10-15"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799440/pdf/nihms-1643496.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38813141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

A SORAFENIB INDUCED MODEL OF GLOMERULAR KIDNEY DISEASE. 索拉非尼诱导的肾小球肾病模型。

Visnyk Kyivs'koho natsional'noho universytetu imeni Tarasa Shevchenka. Biolohiia Pub Date : 2020-01-01 DOI: 10.17721/1728_2748.2020.81.25-31

A Stavniichuk, O Savchuk, Abdul Hye Khan, Wojciech K Jankiewicz, John D Imig

{"title":"A SORAFENIB INDUCED MODEL OF GLOMERULAR KIDNEY DISEASE.","authors":"A Stavniichuk, O Savchuk, Abdul Hye Khan, Wojciech K Jankiewicz, John D Imig","doi":"10.17721/1728_2748.2020.81.25-31","DOIUrl":"https://doi.org/10.17721/1728_2748.2020.81.25-31","url":null,"abstract":"Glomerular injury and proteinuria are important pathophysiological features of chronic kidney disease. In the present study, we provide data on a glomerular injury model that was developed using the cancer chemotherapy drug sorafenib. Sorafenib is a tyrosine kinase inhibitor that acts via the vascular endothelial growth factor (VEGF) signaling pathway and is widely used to treat a variety of cancers. On the other hand, sorafenib causes serious renal side effects in patients including the development of chronic kidney disease. The current study aimed to utilize the nephrotoxic property of sorafenib to develop a rat model for chronic kidney disease. We demonstrate that rats administered sorafenib for 8 weeks along with a high salt diet (8% NaCl enriched) develop hypertension (80mmHg higher systolic blood pressure), proteinuria (75% higher), and 4-fold higher glomerular injury compared to vehicle-treated normal control rat. Sorafenib induced glomerular injury was associated with decreased (20-80% lower) renal mRNA expression of key glomerular structural proteins such as nephrin, podocin, synaptopodin, and podoplanin compared to vehicle-treated normal control rat. Renal cortical endothelial-to-mesenchymal transition (EndoMT) was activated in the sorafenib induced glomerular injury model. In the sorafenib treated rats, the renal EndoMT was evident with 20% lower mRNA expression of an endothelial marker WT-1 and 2 to 3-fold higher expression of mesenchymal markers Col III, FSP-1, α-SMA, and vimentin. In conclusion, we developed a rat pre-clinical chronic kidney disease model that manifest glomerular injury. We further demonstrate that the glomerular injury in this model is associated with decreased renal mRNA expression of key glomerular structural proteins and an activated kidney EndoMT.","PeriodicalId":93155,"journal":{"name":"Visnyk Kyivs'koho natsional'noho universytetu imeni Tarasa Shevchenka. Biolohiia","volume":"81 2","pages":"25-31"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696638/pdf/nihms-1648967.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38654744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2