Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase
Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therap...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6859 |
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| author | Ko-Lin Kuo Chin-Wei Chiang Yi-Ming Arthur Chen Chih-Chin Yu Tzong-Shyuan Lee |
| author_facet | Ko-Lin Kuo Chin-Wei Chiang Yi-Ming Arthur Chen Chih-Chin Yu Tzong-Shyuan Lee |
| author_sort | Ko-Lin Kuo |
| collection | DOAJ |
| description | Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid in renal fibrosis nor whether GNMT is involved in these folic acid-associated mechanisms has been investigated. First, the expression of GNMT was examined in human kidneys with or without obstructive nephropathy. Later, wild-type and <i>GNMT</i> knockout (<i>GNMT<sup>−/−</sup></i>) mice were subjected to unilateral ureteral obstruction (UUO) and then treated with either folic acid or vehicle for 14 days. Renal tubular injury, inflammation, fibrosis, and autophagy were evaluated by histological analysis and Western blotting. We observed increased expression of GNMT in humans with obstructive nephropathy. Furthermore, UUO significantly increased the expression of GNMT in mice; in addition, it caused renal injury as well as the development of both hydronephrosis and tubular injury. These were all alleviated by folic acid treatment. In contrast, <i>GNMT<sup>−/−</sup></i> mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in <i>GNMT<sup>−/−</sup></i> mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target. |
| first_indexed | 2024-03-11T05:33:58Z |
| format | Article |
| id | doaj.art-908c97cbde5844a695f3743911d88dd4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T05:33:58Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-908c97cbde5844a695f3743911d88dd42023-11-17T16:57:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01247685910.3390/ijms24076859Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-MethyltransferaseKo-Lin Kuo0Chin-Wei Chiang1Yi-Ming Arthur Chen2Chih-Chin Yu3Tzong-Shyuan Lee4Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231405, TaiwanDepartment of Physiology, National Yang Ming Chiao Tung University, Taipei 112304, TaiwanGraduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei 24205, TaiwanDivision of Urology, Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231405, TaiwanGraduate Institute, Department of Physiology, College of Medicine, National Taiwan University, Taipei 100, TaiwanFolic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid in renal fibrosis nor whether GNMT is involved in these folic acid-associated mechanisms has been investigated. First, the expression of GNMT was examined in human kidneys with or without obstructive nephropathy. Later, wild-type and <i>GNMT</i> knockout (<i>GNMT<sup>−/−</sup></i>) mice were subjected to unilateral ureteral obstruction (UUO) and then treated with either folic acid or vehicle for 14 days. Renal tubular injury, inflammation, fibrosis, and autophagy were evaluated by histological analysis and Western blotting. We observed increased expression of GNMT in humans with obstructive nephropathy. Furthermore, UUO significantly increased the expression of GNMT in mice; in addition, it caused renal injury as well as the development of both hydronephrosis and tubular injury. These were all alleviated by folic acid treatment. In contrast, <i>GNMT<sup>−/−</sup></i> mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in <i>GNMT<sup>−/−</sup></i> mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target.https://www.mdpi.com/1422-0067/24/7/6859folic acidglycine N-methyltransferaseunilateral ureteral obstruction |
| spellingShingle | Ko-Lin Kuo Chin-Wei Chiang Yi-Ming Arthur Chen Chih-Chin Yu Tzong-Shyuan Lee Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase International Journal of Molecular Sciences folic acid glycine N-methyltransferase unilateral ureteral obstruction |
| title | Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase |
| title_full | Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase |
| title_fullStr | Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase |
| title_full_unstemmed | Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase |
| title_short | Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase |
| title_sort | folic acid ameliorates renal injury in experimental obstructive nephropathy role of glycine n methyltransferase |
| topic | folic acid glycine N-methyltransferase unilateral ureteral obstruction |
| url | https://www.mdpi.com/1422-0067/24/7/6859 |
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