Reduced Renal CSE/CBS/H2S Contributes to the Progress of Lupus Nephritis

SIMPLE SUMMARY: Lupus nephritis is a severe and fatal immune-associated nephritis. The molecular mechanisms underlying lupus nephritis development remain largely unknown. Renal hydrogen sulfide can be produced mainly via two synthetases and is involved in many pathological and physiological processes. Herein, we sought to investigate the roles of renal hydrogen sulfide and its synthetase in lupus nephritis pathogenesis. We found that the expression of two hydrogen sulfide synthetases was downregulated in renal tissues of lupus nephritis patients and lupus mice, which were associated with poor renal outcomes. Moreover, exogenous hydrogen sulfide attenuated renal damage in two mouse models with lupus nephritis. In addition, we further confirmed the increase of renal key transcription factors and T-lymphocyte infiltration in lupus nephritis, which were mitigated after treatment with hydrogen sulfide donors. Our composite data indicated that reduced renal two hydrogen sulfide synthetases contribute to the progress of lupus nephritis, and exogenous hydrogen-sulfide-attenuated renal damage of lupus nephritis may partly be through inhibiting the expression of T-lymphocyte-associated transcription factors. ABSTRACT: The molecular mechanisms underlying lupus nephritis (LN) pathogenesis are not fully understood. Hydrogen sulfide (H2S) is involved in many pathological and physiological processes. We sought to investigate the roles of H2S in LN pathogenesis. H2S synthase cystathionine–lyase (CSE) and cystathionine–synthetase (CBS) expression was downregulated in renal tissues of patients with LN and their levels were associated with LN’s prognosis using the Nephroseq database. Reduced CSE and CBS protein expression in kidney tissues of LN patients and MRL/lpr mice were confirmed by immunohistochemistry. CSE and CBS mRNA levels were reduced in MRL/lpr and pristine- and R848-induced lupus mice. Given that H2S exerts an anti-inflammatory role partly via regulating inflammatory transcription factors (TFs), we analyzed hub TFs by using a bioinformatics approach. It showed that STAT1, RELA, and T-cell-related signaling pathways were enriched in LN. Increased STAT1 and RELA expression were confirmed in renal tissues of LN patients. Treatment of MRL/lpr and pristine mice with H2S donors alleviated systemic lupus erythematosus (SLE) phenotypes and renal injury. H2S donors inhibited RELA level and T-cell infiltration in the kidneys of MRL/lpr and pristine mice. Our data indicated that CSE/CBS/H2S contributes to LN pathogenesis. Supplementation of H2S would be a potential therapeutic strategy for LN.