MicroRNAs Implicated in the Immunopathogenesis of Lupus Nephritis

Table 1

miRNAs implicated in LN pathogenesis.

Cell or tissue type	miR ID(s)	Origin	Strain	Expression	Results	Mechanism(s)	Reference
Renal	21 and 214	R	WKY (anti-Thy1.1)	↑	Expression is induced by TGF-β in tubular epithelial cells in vitro and in renal tissue in vivo	Unknown	[56]
					Overexpression in tubular epithelial cells in vitro decreased E-cadherin expression and increased collagen type I and α-SMA expression	Unknown	[56]
	146a	M	B6.MRLc1	↑	Increased expression positively correlated with IL-1β, IL-10, and CXCL expression, severe glomerular and interstitial lesions, and T cell and macrophage infiltration	Unknown	[59]
		H	—	↑	Glomerular expression positively correlated with estimated GFR and histological activity index	Unknown	[60]
	638	H	—	↑	Tubulointerstitial expression positively correlated with proteinuria and disease activity score	Unknown	[60]
PBMCs	21	H	—	↑	Strongly correlated with disease activity and activated T cells	Unknown	[23]
					Inhibition in vitro reversed the activated T cell phenotype by increasing PDCD4 expression	The 3′ UTR of PDCD4 is a target of miR-21	[23]
	125a	H	—	↓	Underexpression contributes to the elevated expression of RANTES (CCL5) in SLE, increasing T cell recruitment to inflammatory tissues	The 3′ UTR of the RANTES upstream regulator KFL13 is a target of miR-125a, indirectly increasing RANTES expression	[65]
	145	H	—	↓	Decreased expression increased STAT1 expression in SLE patients	The 3′ UTR of STAT1 is a target of miR-145	[64]
	146a	H	—	↓	Inversely correlated with disease activity and IFN-α/β scores	Unknown	[62]
					Overexpression reduced the induction and downstream effects of type I IFN	The 3′ UTR of IRF5 and STAT1 are targets of miR-146a, reducing the induction of type I IFN	[62]
					Promoter variant associated with SLE disease risk	SLE-associated SNP (rs57095329) decreases miR-146a expression levels	[63]
					Positively correlated with GFR, CRP, and other renal function parameters; inversely correlated with proteinuria and SLEDAI	Unknown	[46]
	155	H	—	↓	Positively correlated with GFR, CRP, and other renal function parameters	Unknown	[46]
	224	H	—	↑	Increased expression accelerated T cell activation-induced cell death by suppressing API5 expression in SLE patients	The 3′ UTR of API5 is a target of miR-224	[64]
Mesangial cells	Let-7a	M	NZB/W	↑	Increased expression throughout the lifetime of NZB/W lupus mice; overexpression increased IL-6 expression and IL-6 production in vitro	The 3′ UTR of IL-6 is a target of let-7a; the exact mechanism of let-7a is unknown	[32]
Dendritic cells	155	H	—	↑	Induced by TLR stimulation after miR-155*; overexpression of miR-155 in normal pDCs significantly decreased IFN-α, IFN-β, and TNF-α expression	The 3′ UTR of the type I IFN regulator TAB2 is a target of miR-155, indirectly decreasing IFN-α and IFN-β	[52]
	155*	H	—	↑	Induced by TLR stimulation before miR-155; overexpression of miR-155* in normal pDCs significantly increased IFN-α, IFN-β, and TNF-α expression	The 3′ UTR of the negative IFN regulator IRAKM is a target of miR-155*, indirectly increasing IFN-α and IFN-β	[52]
Splenocytes	15a	M	NZB/W	↑	Increased expression after disease was accelerated by IFN administration; differentially expressed in B cell subsets	Unknown	[69]
	21	M	B6.Sle123	↑	Inhibition increased PDCD4 expression in T cells and reversed splenomegaly, improving overall disease outcome	The 3′ UTR of PDCD4 is a target of miR-21	[70]
		M and H	MRL-lpr	↑	Downregulated DNMT1 expression in T cells	The 3′ UTR of the DNMT1 upstream regulator RASGRP1 is a target of miR-21, indirectly downregulating DNMT1	[71]
	126	H	—	↑	Overexpression contributes to T cell autoreactivity by decreasing DNMT1 expression	The 3′ UTR of DNMT1 is a target of miR-126	[72]
					Overexpression in healthy donors was sufficient for T cell autoreactivity and B cell hyperstimulation, while inhibition in SLE patients resulted in T and B cell inactivation	Unknown	[72]
	142-3p and 142-5p	H	—	↓	Underexpressed in SLE CD4^+ T cells	Dysregulated DNA and histone methylation of the miR-142 promoter	[73]
					Underexpression in CD4^+ T cells increased production of CD84, IL-10, and SAP	The 3′ UTR of CD84 and IL-10 are targets of miR-142-3p; the 3′ UTR of SAP is a target of miR-142-5p	[73]
					Inhibition in healthy donor CD4^+ T cells caused T cell overactivation and B cell hyperstimulation, while overexpression in SLE CD4^+ T cells had the opposite effect	Although CD84 and SAP stimulate T-B cell interactions, the exact mechanism of miR-142 is unknown	[73]
	146a	M	MRL/lpr	↑	Increased expression associated with disease development	Unknown	[74]
	148a	M and H	MRL/lpr	↑	Downregulated DNMT1 expression in T cells	The protein coding region of the DNMT1 transcript is a target of miR-148a	[71]
					Induced overexpression of autoimmune-associated, methylation-sensitive genes in CD4^+ T cells including CD70 and LFA-1	Inhibition of DNMT1 results in DNA hypomethylation and the overexpression of methylation-sensitive genes	[71]
	155	M	MRL/lpr, NZB/W	↑	Increased expression associated with disease development	Unknown	[74]

Abbreviations: H: human; M: mouse; R: rat.
↑: increased expression; ↓: decreased expression.
α-SMA: α-smooth muscle actin; API: apoptosis inhibitory protein; CRP: C-reactive protein; DNMT: DNA methyltransferase; GFR: glomerular filtration rate; IFN: interferon; IL: interleukin; IRAK: IL-1 receptor-associated kinase, IRF: interferon regulatory factor; NZB/W: New Zealand Black/White; PBMCs: peripheral blood mononuclear cells; pDC: plasmacytoid dendritic cell; SNP: single-nucleotide polymorphism; PDCD: programmed cell death; SLE: systemic lupus erythematosus; SLEDAI: SLE Disease Associated Index; STAT: signal transducer and activator of transcription; TGF-β: transforming growth factor-β; TTP: tristetraprolin.