The Role and Mechanism of Lysine Methyltransferase and Arginine Methyltransferase in Kidney Diseases

Abstract

Methylation can occur in both histones and non-histones. Key lysine and arginine methyltransferases under investigation for renal disease treatment include enhancer of zeste homolog 2 (EZH2), G9a, disruptor of telomeric silencing 1-like protein (DOT1L), and protein arginine methyltransferases (PRMT) 1 and 5. Recent studies have shown that methyltransferases expression and activity are also increased in several animal models of kidney injury, such as acute kidney injury(AKI), obstructive nephropathy, diabetic nephropathy and lupus nephritis. The inhibition of most methyltransferases can attenuate kidney injury, while the role of methyltransferase in different animal models remains controversial. In this article, we summarize the role and mechanism of lysine methyltransferase and arginine methyltransferase in various kidney diseases and highlight methyltransferase as a potential therapeutic target for kidney diseases.

Keywords: acute kidney injury; arginine methyltransferase; chronic kidney diseases; epigenetic modification; lysine methyltransferase; renal cell carcinoma.

FIGURE 1

Role and mechanism of EZH2 inhibition in AKI. EZH2 inhibition plays a protective role in acute kidney injury by preserving the expression of RKIP, E-cadherin, TIMP-2 and TIMP-3, and repressing the activation of multiple fibrosis and inflammatory signaling pathways, including NF-κB, ERK1/2, p38 and ALK5/Smad2/3. AbbreviationsAKI, acute kidney injury; EZH2, enhancer of zeste homolog 2; TIMP-2, metalloproteinase-2; TIMP-3, metalloproteinase-3; RKIP, raf kinase inhibitor protein; NF-κB, nuclear factor-κB; ERK, extracellular signal-regulated kinase.

FIGURE 2

Role and mechanism of DOT1L inhibition in renal fibrosis. Inhibition of DOT1L promotes renal fibrosis by up-regulating ET1. In contrast, Inhibition of DOT1L alleviates renal fibrosis by inhibiting multiple fibrosis pathways (including Smad3, EGFR, PDGFR and NF-κB pathway), up-regulating the expressions of renal protective factors such as PTEN, Klotho and Smad7,2, and preventing the generation of ROS via the PI3K/Akt pathway. AbbreviationsDOT1L, disruptor of telomeric silencing 1-like protein; EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; NF-κB, nuclear factor-κB; PTEN, tensin homolog deleted on chromosome 10; STAT3, signal transducer and activator of transcription 3; ET1, endothelin 1.

FIGURE 3

Role of histone arginine methyltransferases in various renal diseases. PRMT1 increases oxidative stress and promotes diabetic kidney injury by regulating the metabolic axis of PRMT1-AMDA-DDAH1. PRMT1 overexpression promotes endoplasmic reticulum (ER), thus inducing mesangial cell apoptosis in DN, PRMT1 knockdown reduces the injury. Inhibition of PRMT1 can inhibit the activation of TGF-β/Smad3 signaling pathway and alleviate renal fibrosis. PRMT1 has also been shown to affect NO production and reduce renal fibrosis through AMDA, and inhibition of PRMT1 can increase this pathological progression. PRMT5 interacts with LINC01138 to enhance protein stability and methylation of SREBP1, further mediating lipid desaturation and promoting RCC cell proliferation. PRMT5 is also involved in ischemia- and hypoxia-induced oxidative stress and pyroptosis via activation of the Nrf2/HO-1 signal pathway. AbbreviationsPRMT, protein arginine methyltransferases; DDAH, dimethylarginine dimethylaminohydrolase; SREBP1, sterol regulatory element-binding protein 1; RCC, renal cell carcinoma; Nrf2, NF-E2-related factor; HO-1, heme oxygenase-1; ADMA, asymmetrical di-methylarginine.