Academic Journal
Sodium thiosulfate treatment rescues hyperglycaemia-induced pronephros damage in zebrafish by upregulating nitric oxide signalling.
| Title: | Sodium thiosulfate treatment rescues hyperglycaemia-induced pronephros damage in zebrafish by upregulating nitric oxide signalling. |
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| Authors: | Ott H; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Bennewitz K; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Zhang X; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Prianichnikova M; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Sticht C; NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Poschet G; Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany., Kroll J; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. |
| Source: | The Journal of physiology [J Physiol] 2026 Jun; Vol. 604 (11), pp. 4247-4260. Date of Electronic Publication: 2024 Sep 12. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Cambridge Univ. Press Country of Publication: England NLM ID: 0266262 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-7793 (Electronic) Linking ISSN: 00223751 NLM ISO Abbreviation: J Physiol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Blackwell : Cambridge Univ. Press Original Publication: London, Cambridge Univ. Press. |
| MeSH Terms: | Nitric Oxide*/metabolism , Hyperglycemia*/metabolism , Hyperglycemia*/drug therapy , Thiosulfates*/pharmacology , Thiosulfates*/therapeutic use , Pronephros*/drug effects , Pronephros*/metabolism , Pronephros*/pathology, Signal Transduction/drug effects ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Animals ; Zebrafish ; Up-Regulation |
| Abstract: | Sodium thiosulfate (STS) is gaining increasing attention in research for its potential therapeutic applications across a spectrum of disease processes beyond its current uses. However, the precise mechanisms of action remain incompletely understood. We investigated the efficacy of STS in treating hyperglycaemia-induced pronephros damage in zebrafish to gain further insight into the underlying mechanisms. Hyperglycaemia was induced in zebrafish by suppressing the pdx1 transcription factor, which plays a crucial role in maintaining physiological pancreatic function. STS was administered by introducing it into the medium of zebrafish larvae. The pronephros structure was analysed at 48 h post-fertilization. Metabolomic profiling and RNA sequencing were conducted on groups exposed to various experimental conditions. Our findings reveal a downregulation of nitric oxide (NO) signalling in zebrafish with a knocked-down pdx1 gene, both metabolomically and transcriptionally. Notably, treatment with STS led to a compensatory upregulation of the NO signalling, ultimately resulting in the rescue of the pronephros structure. Our study provides compelling evidence that targeting NO metabolism by the administration of STS offers a promising strategy for addressing hyperglycaemia-induced organ damage. These findings underscore the potential of STS as a promising therapeutic agent for diabetic complications and warrant further investigation of its clinical applications. KEY POINTS: Sodium thiosulfate (STS) is increasingly drawing attention in research for its potential therapeutic applications across a spectrum of disease processes. Here, we demonstrate that STS treatment rescues hyperglycaemia-induced pronephros damage in zebrafish. We identified upregulation of nitric oxide signalling as the major driver behind STS-mediated rescue. Our data suggest that STS offers a promising strategy for addressing hyperglycaemia-induced organ damage, including diabetic nephropathy. (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.) |
| References: | Aldamiz‐Echevarria, L., & Andrade, F. (2012). Asymmetric dimethylarginine, endothelial dysfunction and renal disease. International Journal of Molecular Sciences, 13(9), 11288–11311. Ali, Z., Zang, J., Lagali, N., Schmitner, N., Salvenmoser, W., Mukwaya, A., Neuhauss, S. C. F., Jensen, L. D., & Kimmel, R. A. (2020). Photoreceptor degeneration accompanies vascular changes in a zebrafish model of diabetic retinopathy. Investigative Ophthalmology & Visual Science, 61(2), 43. Backman, T. W. H., & Girke, T. (2016). systemPipeR: NGS workflow and report generation environment. Biomedical Central Bioinformatics [Electronic Resource], 17, 388. Bijarnia, R. K., Bachtler, M., Chandak, P. G., van Goor, H., & Pasch, A. (2015). Sodium thiosulfate ameliorates oxidative stress and preserves renal function in hyperoxaluric rats. PLoS ONE, 10(4), e0124881. Bray, N. L., Pimentel, H., Melsted, P., & Pachter, L. (2016). Near‐optimal probabilistic RNA‐seq quantification. Nature Biotechnology, 34(5), 525–527. Brock, P. R., Maibach, R., Childs, M., Rajput, K., Roebuck, D., Sullivan, M. J., Laithier, V., Ronghe, M., Dall'Igna, P., Hiyama, E., Brichard, B., Skeen, J., Mateos, M. E., Capra, M., Rangaswami, A. A., Ansari, M., Rechnitzer, C., Veal, G. J., Covezzoli A., … Neuwelt, E. A. (2018). Sodium thiosulfate for protection from cisplatin‐induced hearing loss. New England Journal of Medicine, 378(25), 2376–2385. Bucci, M., Papapetropoulos, A., Vellecco, V., Zhou, Z., Pyriochou, A., Roussos, C., Roviezzo, F., Brancaleone, V., & Cirino, G. (2010). Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(10), 1998–2004. Buonvino, S., Arciero, I., & Melino, S. (2022). Thiosulfate‐cyanide sulfurtransferase a mitochondrial essential enzyme: From cell metabolism to the biotechnological applications. International Journal of Molecular Sciences, 23(15), 8452. Carlson, M. (2019). org.Dr.eg.db: Genome Wide Annotation for Zebrafish. R Package Version 3.8.2 http://bioconductor.org/packages/release/data/annotation/html/org.Dr.eg.db.html. Cheng, H., Wang, H., Fan, X., Paueksakon, P., & Harris, R. C. (2012). Improvement of endothelial nitric oxide synthase activity retards the progression of diabetic nephropathy in db/db mice. Kidney International, 82(11), 1176–1183. Cirino, G., Szabo, C., & Papapetropoulos, A. (2023). Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs. Physiological Reviews, 103(1), 31–276. Coletta, C., Papapetropoulos, A., Erdelyi, K., Olah, G., Modis, K., Panopoulos, P., Asimakopoulou, A., Gero, D., Sharina, I., Martin, E., & Szabo, C. (2012). Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium‐dependent vasorelaxation. Proceedings of the National Academy of Sciences of the United States of America, 109(23), 9161–9166. Drummond, I. A. (2000). The zebrafish pronephros: A genetic system for studies of kidney development. Pediatric Nephrology, 14(5), 428–435. Gegner, H. M., Mechtel, N., Heidenreich, E., Wirth, A., Cortizo, F. G., Bennewitz, K., Fleming, T., Andresen, C., Freichel, M., Teleman, A. A., Kroll, J., Hell, R., & Poschet, G. (2022). Deep metabolic profiling assessment of tissue extraction protocols for three model organisms. Frontiers in Chemistry, 10, 869732. Gossett, C., Suppadungsuk, S., Krisanapan, P., Tangpanithandee, S., Thongprayoon, C., Mao, M. A., & Cheungpasitporn, W. (2023). Sodium thiosulfate for calciphylaxis treatment in patients on peritoneal dialysis: A systematic review. Medicina (Kaunas, Lithuania), 59(7), 1306. He, B., Zhang, Z., Huang, Z., Duan, X., Wang, Y., Cao, J., Li, L., He, K., Nice, E. C., He, W., Gao, W., & Shen, Z. (2023). Protein persulfidation: Rewiring the hydrogen sulfide signaling in cell stress response. Biochemical Pharmacology, 209, 115444. Heckler, K., & Kroll, J. (2017). Zebrafish as a model for the study of microvascular complications of diabetes and their mechanisms. International Journal of Molecular Sciences, 18(9), 2002. Hsu, C. N., Hou, C. Y., Chang‐Chien, G. P., Lin, S., Yang, H. W., & Tain, Y. L. (2022). Sodium thiosulfate improves hypertension in rats with adenine‐induced chronic kidney disease. Antioxidants (Basel), 11(1), 147. Ichimura, K., Bubenshchikova, E., Powell, R., Fukuyo, Y., Nakamura, T., Tran, U., Oda, S., Tanaka, M., Wessely, O., Kurihara, H., Sakai, T., & Obara, T. (2012). A comparative analysis of glomerulus development in the pronephros of medaka and zebrafish. PLoS ONE, 7(9), e45286. Iciek, M., & Wlodek, L. (2001). Biosynthesis and biological properties of compounds containing highly reactive, reduced sulfane sulfur. Polish Journal of Pharmacology, 53(3), 215–225. Jin, S., Teng, X., Xiao, L., Xue, H., Guo, Q., Duan, X., Chen, Y., & Wu, Y. (2017). Hydrogen sulfide ameliorated L‐NAME‐induced hypertensive heart disease by the Akt/eNOS/NO pathway. Experimental Biology and Medicine (Maywood, N.J.), 242(18), 1831–1841. Jorgens, K., Stoll, S. J., Pohl, J., Fleming, T. H., Sticht, C., Nawroth, P. P., Hammes, H. P., & Kroll, J. (2015). High tissue glucose alters intersomitic blood vessels in zebrafish via methylglyoxal targeting the VEGF receptor signaling cascade. Diabetes, 64(1), 213–225. Kimura, Y., Goto, Y., & Kimura, H. (2010). Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxidants & Redox Signaling, 12(1), 1–13. Kondo, K., Bhushan, S., King, A. L., Prabhu, S. D., Hamid, T., Koenig, S., Murohara, T., Predmore, B. L., Gojon, G., Sr., Gojon, G., Jr., Wang, R., Karusula, N., Nicholson, C. K., Calvert, J. W., & Lefer, D. J. (2013). H₂S protects against pressure overload‐induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation, 127(10), 1116–1127. Lin, F., Yang, Y., Wei, S., Huang, X., Peng, Z., Ke, X., Zeng, Z., & Song, Y. (2020). Hydrogen sulfide protects against high glucose‐induced human umbilical vein endothelial cell injury through activating PI3K/Akt/eNOS Pathway. Drug Design, Development and Therapy, 14, 621–633. Mohan, D., Balasubramanian, E. D., Ravindran, S., & Kurian, G. A. (2017). Renal mitochondria can withstand hypoxic/ischemic injury secondary to renal failure in uremic rats pretreated with sodium thiosulfate. Indian Journal of Pharmacology, 49(4), 317–321. Mustafa, A. K., Sikka, G., Gazi, S. K., Steppan, J., Jung, S. M., Bhunia, A. K., Barodka, V. M., Gazi, F. K., Barrow, R. K., Wang, R., Amzel, L. M., Berkowitz, D. E., & Snyder, S. H. (2011). Hydrogen sulfide as endothelium‐derived hyperpolarizing factor sulfhydrates potassium channels. Circulation Research, 109(11), 1259–1268. Nakagawa, T., Sato, W., Glushakova, O., Heinig, M., Clarke, T., Campbell‐Thompson, M., Yuzawa, Y., Atkinson, M. A., Johnson, R. J., & Croker, B. (2007). Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. Journal of the American Society of Nephrology, 18(2), 539–550. Nguyen, I. T. N., Klooster, A., Minnion, M., Feelisch, M., Verhaar, M. C., van Goor, H., & Joles, J. A. (2020). Sodium thiosulfate improves renal function and oxygenation in L‐NNA‐induced hypertension in rats. Kidney International, 98(2), 366–377. Papapetropoulos, A., Pyriochou, A., Altaany, Z., Yang, G., Marazioti, A., Zhou, Z., Jeschke, M. G., Branski, L. K., Herndon, D. N., Wang, R., & Szabo, C. (2009). Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proceedings of the National Academy of Sciences of the United States of America, 106(51), 21972–21977. Poureetezadi, S. J., & Wingert, R. A. (2016). Little fish, big catch: Zebrafish as a model for kidney disease. Kidney International, 89(6), 1204–1210. Ravindran, S., Boovarahan, S. R., Shanmugam, K., Vedarathinam, R. C., & Kurian, G. A. (2017). Sodium thiosulfate preconditioning ameliorates ischemia/reperfusion injury in rat hearts via reduction of oxidative stress and apoptosis. Cardiovascular Drugs and Therapy, 31(5–6), 511–524. Ravindran, S., Jahir Hussain, S., Boovarahan, S. R., & Kurian, G. A. (2017). Sodium thiosulfate post‐conditioning protects rat hearts against ischemia reperfusion injury via reduction of apoptosis and oxidative stress. Chemico‐Biological Interactions, 274, 24–34. Ravindran, S., & Kurian, G. A. (2019). Preconditioning the rat heart with sodium thiosulfate preserved the mitochondria in response to ischemia‐reperfusion injury. Journal of Bioenergetics and Biomembranes, 51(3), 189–201. Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). limma powers differential expression analyses for RNA‐sequencing and microarray studies. Nucleic Acids Research, 43(7), e47. Sharma, K. R., Heckler, K., Stoll, S. J., Hillebrands, J. L., Kynast, K., Herpel, E., Porubsky, S., Elger, M., Hadaschik, B., Bieback, K., Hammes, H. P., Nawroth, P. P., & Kroll, J. (2016). ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions. Scientific Reports, 6, 37172. She, J., Yuan, Z., Wu, Y., Chen, J., & Kroll, J. (2018). Targeting erythropoietin protects against proteinuria in type 2 diabetic patients and in zebrafish. Molecular Metabolism, 8, 189–202. Snijder, P. M., Frenay, A. R., Koning, A. M., Bachtler, M., Pasch, A., Kwakernaak, A. J., van den Berg, E., Bos, E. M., Hillebrands, J. L., Navis, G., Leuvenink, H. G., & van Goor, H. (2014). Sodium thiosulfate attenuates angiotensin II‐induced hypertension, proteinuria and renal damage. Nitric Oxide, 42, 87–98. Song, K., Wang, F., Li, Q., Shi, Y. B., Zheng, H. F., Peng, H., Shen, H. Y., Liu, C. F., & Hu, L. F. (2014). Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney International, 85(6), 1318–1329. Tessari, P. (2015). Nitric oxide in the normal kidney and in patients with diabetic nephropathy. Journal of Nephrology, 28(3), 257–268. Wiggenhauser, L. M., Metzger, L., Bennewitz, K., Soleymani, S., Boger, M., Tabler, C. T., Hausser, I., Sticht, C., Wohlfart, P., Volk, N., Heidenreich, E., Buettner, M., Hammes, H. P., & Kroll, J. (2022). pdx1 knockout leads to a diabetic nephropathy‐ like phenotype in zebrafish and identifies phosphatidylethanolamine as metabolite promoting early diabetic kidney damage. Diabetes, 71(5), 1073–1080. Wiggenhauser, L. M., Qi, H., Stoll, S. J., Metzger, L., Bennewitz, K., Poschet, G., Krenning, G., Hillebrands, J. L., Hammes, H. P., & Kroll, J. (2020). Activation of retinal angiogenesis in hyperglycemic pdx1 (−/−) zebrafish mutants. Diabetes, 69(5), 1020–1031. Wu, T., Hu, E., Xu, S., Chen, M., Guo, P., Dai, Z., Feng, T., Zhou, L., Tang, W., Zhan, L., Fu, X., Liu, S., Bo, X., & Yu, G. (2021). clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Cambridge), 2(3), 100141. Xue, X., Ling, X., Xi, W., Wang, P., Sun, J., Yang, Q., & Xiao, J. (2020). Exogenous hydrogen sulfide reduces atrial remodeling and atrial fibrillation induced by diabetes mellitus via activation of the PI3K/Akt/eNOS pathway. Molecular Medicine Reports, 22(3), 1759–1766. Yang, G., Wu, L., Bryan, S., Khaper, N., Mani, S., & Wang, R. (2010). Cystathionine gamma‐lyase deficiency and overproliferation of smooth muscle cells. Cardiovascular Research, 86(3), 487–495. Zanardo, R. C., Brancaleone, V., Distrutti, E., Fiorucci, S., Cirino, G., & Wallace, J. L. (2006). Hydrogen sulfide is an endogenous modulator of leukocyte‐mediated inflammation. Federation of American Societies for Experimental Biology Journal, 20(12), 2118–2120. Zhang, M. Y., Dugbartey, G. J., Juriasingani, S., & Sener, A. (2021). Hydrogen sulfide metabolite, sodium thiosulfate: Clinical applications and underlying molecular mechanisms. International Journal of Molecular Sciences, 22(12), 6452. |
| Grant Information: | IRTG1874 DIAMICOM Deutsche Forschungsgemeinschaft (DFG); 517361638 Deutsche Forschungsgemeinschaft (DFG) |
| Contributed Indexing: | Keywords: diabetes mellitus; nitric oxide; sodium thiosulfate; zebrafish |
| Substance Nomenclature: | 31C4KY9ESH (Nitric Oxide) 0 (Thiosulfates) HX1032V43M (sodium thiosulfate) 0 (Zebrafish Proteins) 0 (Homeodomain Proteins) 0 (Trans-Activators) 0 (pancreatic and duodenal homeobox 1 protein) |
| Entry Date(s): | Date Created: 20240912 Date Completed: 20260601 Latest Revision: 20260601 |
| Update Code: | 20260601 |
| DOI: | 10.1113/JP286398 |
| PMID: | 39264236 |
| Database: | MEDLINE |
| ISSN: | 1469-7793 |
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| DOI: | 10.1113/JP286398 |