Abstract
Suppressor of cytokine signaling 1 (SOCS1) participates in renal fibrosis by downregulating Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1)-mediated cytokine signaling. Recently, it was found that anti-double-stranded DNA (dsDNA) IgG induces the synthesis of profibrotic cytokines by renal cells. To explore the potential effect of anti-dsDNA IgG on SOCS1-mediated renal fibrosis, kidney tissues were collected from patients with lupus nephritis (LN) as well as MRL/lpr lupus-prone mice. The SOCS1 expression was evaluated in tissue samples. In addition, SCID mice were injected with anti-dsDNA IgG, followed by evaluation of SOCS1 levels. Renal resident cells were cultured in vitro, receiving the stimulation of anti-dsDNA IgG and then the measurement of SOCS1, JAK2, STAT1α, and profibrotic cytokines. Moreover, the binding of anti-dsDNA IgG to SOCS1 kinase inhibitory region (KIR) peptide was analyzed by surface plasmon resonance. We found that SOCS1 expression was inhibited, but JAK2/STAT1 activation was prominent in the kidney tissues of patients with LN, MRL/lpr mice, or anti-dsDNA IgG-injected SCID mice. The cultured renal cells also showed SOCS1 downregulation, JAK2/STAT1 activation, and profibrotic cytokine promotion upon anti-dsDNA IgG stimulation. Surprisingly, anti-dsDNA IgG showed high affinity to KIR peptide and competed with JAK2 loop for KIR. Additionally, a DNA-mimicking peptide (ALW) blocked the binding of anti-dsDNA IgG to KIR, and even partially abrogated the activation of JAK2/STAT1α signals and the expression of profibrotic cytokines in SCID mice. In conclusion, anti-dsDNA IgG downregulates SOCS1 expression, activates JAK2/STAT1 signals, and contributes to renal fibrosis; its peptide blockade may restore the SOCS1 inhibitory effect on the production of profibrotic cytokine, and finally ameliorate renal fibrosis in LN.
Highlights
As the most common internal complication in patients with systemic lupus erythematosus (SLE) [1], lupus nephritis (LN) is essentially a chronic inflammation in kidneys
Suppressor of cytokine signaling 1 (SOCS1) expression decreases significantly, whereas the expression of profibrotic genes increases in kidney biopsies from patients with LN [27]. miR-150 can promote renal fibrosis in LN by inhibiting both mRNA and protein levels of SOCS1 [27]. These results strongly suggested that SOCS1 plays an important role in the pathogenesis of SLE as well as renal fibrosis of LN
The purpose of this study was to investigate the potential effect of anti-double-stranded DNA (dsDNA) IgG on the regulation of SOCS1 signals and the molecular mechanism underlying SOCS1-kinase inhibitory region (KIR) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) interaction in the pathogenesis of renal fibrosis
Summary
As the most common internal complication in patients with systemic lupus erythematosus (SLE) [1], lupus nephritis (LN) is essentially a chronic inflammation in kidneys. LN is classified into Class I to Class VI according to pathological patterns [2], renal fibrosis is definitely the common final outcome at the end stage [1]. The fibrotic lesions are associated strongly with poor outcome of patients with LN [3]. During the progression of renal fibrosis, profibrotic cytokines are continuously released, and enhance the phenotype changes of resident cells as well as the accumulation of extracellular matrix [3, 4]. Elucidation of the pathogenesis of renal fibrosis, especially the regulation of profibrotic cytokines, is important in the development of therapeutic strategies for patients with LN
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