SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4
Abstract Background Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SD...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04181-9 |
| _version_ | 1797822681373999104 |
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| author | Yanzhe Wang Ming Wu Dongping Chen Bo Tan Pinglan Lin Di Huang Chaoyang Ye |
| author_facet | Yanzhe Wang Ming Wu Dongping Chen Bo Tan Pinglan Lin Di Huang Chaoyang Ye |
| author_sort | Yanzhe Wang |
| collection | DOAJ |
| description | Abstract Background Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. Methods Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia–reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. Results We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p < 0.001) in mouse kidneys was observed after renal injection which was assessed by LC–MS/MS. We further showed that intrarenal administration of SDMA attenuated renal fibrosis in UIRI induced mouse fibrotic kidneys. Through RNA sequencing analysis, we found that the expression of STAT4 was reduced by SDMA in UUO kidneys, which was further confirmed by quantitative PCR and Western blotting analysis in mouse fibrotic kidneys and renal cells. Inhibition of STAT4 by berbamine dihydrochloride (0.3 mg/ml or 3.3 mg/ml) or siRNA reduced the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Furthermore, blockage of STAT4 attenuated the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells. Conversely, overexpression of STAT4 reversed the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells. Conclusion Taken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4. |
| first_indexed | 2024-03-13T10:12:42Z |
| format | Article |
| id | doaj.art-8e0882e8d5854398b70370375ed8d164 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-13T10:12:42Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-8e0882e8d5854398b70370375ed8d1642023-05-21T11:25:43ZengBMCJournal of Translational Medicine1479-58762023-05-0121111310.1186/s12967-023-04181-9SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4Yanzhe Wang0Ming Wu1Dongping Chen2Bo Tan3Pinglan Lin4Di Huang5Chaoyang Ye6Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineDepartment of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineDepartment of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineClinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineDepartment of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineDepartment of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineDepartment of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineAbstract Background Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. Methods Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia–reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. Results We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p < 0.001) in mouse kidneys was observed after renal injection which was assessed by LC–MS/MS. We further showed that intrarenal administration of SDMA attenuated renal fibrosis in UIRI induced mouse fibrotic kidneys. Through RNA sequencing analysis, we found that the expression of STAT4 was reduced by SDMA in UUO kidneys, which was further confirmed by quantitative PCR and Western blotting analysis in mouse fibrotic kidneys and renal cells. Inhibition of STAT4 by berbamine dihydrochloride (0.3 mg/ml or 3.3 mg/ml) or siRNA reduced the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Furthermore, blockage of STAT4 attenuated the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells. Conversely, overexpression of STAT4 reversed the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells. Conclusion Taken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4.https://doi.org/10.1186/s12967-023-04181-9SDMARenal fibrosisSTAT4 |
| spellingShingle | Yanzhe Wang Ming Wu Dongping Chen Bo Tan Pinglan Lin Di Huang Chaoyang Ye SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4 Journal of Translational Medicine SDMA Renal fibrosis STAT4 |
| title | SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4 |
| title_full | SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4 |
| title_fullStr | SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4 |
| title_full_unstemmed | SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4 |
| title_short | SDMA attenuates renal tubulointerstitial fibrosis through inhibition of STAT4 |
| title_sort | sdma attenuates renal tubulointerstitial fibrosis through inhibition of stat4 |
| topic | SDMA Renal fibrosis STAT4 |
| url | https://doi.org/10.1186/s12967-023-04181-9 |
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