Protein arginine methyltransferase 3 inhibits renal tubulointerstitial fibrosis through asymmetric dimethylarginine

Yanzhe Wang; Ming Wu; Feng Yang; Junyan Lin; Li Zhang; Meijie Yuan; Dongping Chen; Bo Tan; Di Huang; Chaoyang Ye

doi:10.3389/fmed.2022.995917

Protein arginine methyltransferase 3 inhibits renal tubulointerstitial fibrosis through asymmetric dimethylarginine

Front Med (Lausanne). 2022 Sep 13:9:995917. doi: 10.3389/fmed.2022.995917. eCollection 2022.

Authors

Yanzhe Wang^{1

2

3}, Ming Wu^{1

2

3}, Feng Yang^{1

2

3}, Junyan Lin^{1

2

3}, Li Zhang⁴, Meijie Yuan^{1

2

3

5}, Dongping Chen^{1

2

3}, Bo Tan⁶, Di Huang^{1

2

3}, Chaoyang Ye^{1

2

3}

Affiliations

¹ Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
³ Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China.
⁴ Department of Pediatrics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁵ Department of Nephrology, The First Hospital of Hebei Medical University, Shijiazhuang, China.
⁶ Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Abstract

Mammalian protein arginine methyltransferase 3 (PRMT3) catalyzes the monomethylation and dimethylation of the arginine residues of proteins. The role of PRMT3 in renal fibrosis is currently unknown. We aimed to study the role of PRMT3 in renal fibrosis and explored its underlying mechanisms. Quantitative PCR analysis and Western blotting analysis showed that the expression of PRMT3 was up-regulated in unilateral ureteral obstruction (UUO) mouse kidneys. Knockout of Prmt3 gene enhanced interstitial fibrosis in UUO kidneys as shown by Masson staining and Western blotting analysis the expression of pro-fibrotic markers. The production of asymmetric dimethylarginine (ADMA) was increased in wide type UUO kidneys but not further increased in Prmt3 knockout UUO kidneys. Administration of exogeneous ADMA in UUO kidneys blocked the enhanced renal interstitial fibrosis in Prmt3 mutant mice. Moreover, genetic deletion of Prmt3 gene increased blood urea nitrogen levels and renal deposition of collagen in folic acid injected mice. We conclude that PRMT3 inhibits renal tubulointerstitial fibrosis through elevating renal ADMA levels.

Keywords: ADMA; arginine methyltransferase; chronic kidney disease; fibrosis; obstructive nephropathy.