Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase

Author:

Kuo Ko-Lin123ORCID,Chiang Chin-Wei4,Chen Yi-Ming Arthur5,Yu Chih-Chin67ORCID,Lee Tzong-Shyuan8ORCID

Affiliation:

1. Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231405, Taiwan

2. School of Medicine, Buddhist Tzu Chi University, Hualien 97004, Taiwan

3. School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 97004, Taiwan

4. Department of Physiology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan

5. Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei 24205, Taiwan

6. Division of Urology, Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231405, Taiwan

7. College of Medicine, Tzu Chi University, Hualien 97004, Taiwan

8. Graduate Institute, Department of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan

Abstract

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 GNMT knockout (GNMT−/−) 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, GNMT−/− mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in GNMT−/− mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target.

Funder

Ministry of Science and Technology

Taipei Tzu Chi Hospital

Buddhist Tzu Chi Medical Foundation, Taiwan

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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