Study suggests sodium bicarbonate cotransporter 2 as promising target for rheumatoid arthritis therapy

A recent study featured in Biomedicine & Pharmacotherapy has shed light on the intricate role of bicarbonate in exacerbating protein citrullination and inflammation associated with rheumatoid arthritis (RA) through the sodium bicarbonate cotransporter 2 (NBCe2). Moreover, researchers also noted the role of iguratimod (IGU) as a potential therapeutic agent that effectively mitigates RA-related protein citrullination and inflammation by suppressing the expression of NBCe2. 

The study, conducted by Dr. Peng and his team, recruited 20 RA patients. The findings showed that the production of citrullinated proteins by peripheral blood neutrophils, rather than peripheral blood mononuclear cells, was elevated with increasing bicarbonate levels, correlating with increased expression levels of NBCe2. Moreover, tumor necrosis factor-alpha (TNF-α) was found to enhance NBCe2 expression in neutrophils of RA patients. Furthermore, the researchers noted the inhibitory effects of IGU on neutrophil NBCe2 and citrullinated histone H3 (cit-H3) levels, as well as its impact on neutrophil and PBMC migration. Additionally, the ability  IGU to inhibit neutrophil NBCe2 and citrullinated histone H3 (cit-H3) levels, as well as its effectiveness in reducing neutrophil and PBMC migration, and its capacity to suppress the secretion of interleukin 6 (IL-6), TNF-α, and metalloproteinase-9 (MMP-9) from neutrophil-like differentiated HL-60 cells is comparable to that of methotrexate (MTX), and dexamethasone at specific doses. 

Originally identified in the human testis and heart, NBCe2 has since been detected in various sites. It serves as a key regulator of sodium and bicarbonate transport, impacting intracellular, extracellular, interstitial, and ultimately plasma pH levels. Notably, NBCe2 is prominently located within the renal-collecting duct and proximal tubule of both human and rodent kidneys. Disruption of the Slc4a5 gene, responsible for encoding the electrogenic sodium bicarbonate cotransporter NBCe2, induces substantial remodeling of choroid plexus epithelial cells. This remodeling encompasses irregularities in mitochondrial distribution, altered expression of cytoskeletal proteins, and polarity disturbances in ion transporters. 

The present study provides compelling evidence that bicarbonate facilitates protein citrullination and inflammation in RA through the action of NBCe2 and highlights the inhibitory effects of IGU on RA-related protein citrullination and inflammation, achieved by downregulating NBCe2 expression. These findings not only underscore the significance of NBCe2 in RA pathogenesis but also propose it as a promising novel therapeutic target for the treatment of RA. Further exploration of targeted interventions holds great potential for advancing RA management and improving patient outcomes. 


  1. Peng T, Li B, Bi L, Zhang F. Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis. Biomed Pharmacother. 2024 Apr 17;174:116551. 
  1. Felder RA, Jose PA, Xu P, Gildea JJ. The Renal Sodium Bicarbonate Cotransporter NBCe2: Is It a Major Contributor to Sodium and pH Homeostasis? Curr Hypertens Rep. 2016 Sep;18(9):71.