Inflammatory Pathways of Sulfonamide Diuretics: Insights into SLC12A Cl^- Symporters and Additional Targets

Thiazide, thiazide-like, and loop diuretics are primarily known for inhibiting members of the SLC12A family of Cl^- transporters, which include the Na+Cl^- cotransporter (NCC), Na⁺K⁺2Cl^- cotransporters (NKCC1 and NKCC2) and K⁺Cl^- symporters (KCC1-4). While the main pharmacological effect of these diuretics is diuresis, achieved by promoting the excretion of excess water and salt through the kidneys, they have intriguing pharmacological effects beyond their traditional ones which cannot be solely attributed to their effects on renal salt transport. Of particular interest is their role in modulating inflammatory processes. These diuretics appear to exert both pro- and anti-inflammatory effects, potentially by influencing various pathways involved in immune responses. For example, NKCC1 has been implicated in the regulation of pro-inflammatory cytokines, such as interleukin-1β (IL1β), interleukin-8 (IL8) and tumor necrosis factor α (TNFα), which are critical mediators of immune cell activity during inflammation. The underlying mechanisms through which NKCC1 contributes to inflammation may involve key signaling pathways, such as that mediated by the nuclear factor kappa B (NFκB). This pathway is crucial for the activation and assembly of the inflammasome, as well as for regulating the phagocytic activity of immune cells. In addition, NKCC1 can control (or be controlled) by reactive oxygen species and oxidative stress, which contribute to the pathogenesis of various inflammatory conditions as well. Diuretics may help mitigate inflammation-related tissue damage by scavenging reactive oxygen species and boosting antioxidant defenses, thereby restoring redox balance in inflamed tissues. Despite these intriguing effects, the precise molecular pathways through which thiazide, thiazide-like and loop diuretics may modulate inflammatory responses remain poorly understood and warrant further investigation. This aspect of their pharmacological profile highlights their potential for therapeutic use beyond the scope of traditional diuretic functions.