Ozone-induced renal homeostasis disruption in diabetic mice: The role of Th17/Treg imbalance and drug intervention.

Ground-level ozone pollution has emerged as a significant environmental risk factor for diabetic kidney diseases, yet the underlying mechanisms and potential interventions remain poorly defined. This study investigated the nephrotoxic effects of ozone in a diabetic model, wherein male db/db mice were exposed to ozone (0.25 or 1.0 ppm) for 8 weeks. Moreover, dapagliflozin (DAPA) and Yishen Huashi Granules (YSHS), pharmaceutical agents commonly used to treat metabolic and renal diseases, were applied to investigate their therapeutic potential against ozone-caused kidney insult. Our data demonstrated that ozone exposure could exacerbate hyperglycemia and structural renal damage, including glomerular basement membrane thickening, podocyte fusion, and fibrogenesis. Furthermore, ozone exposure disrupted the splenic Th17/Treg balance, enhanced IL-17 production, and promoted renal inflammation through upregulating RORγt/IL-17A signaling pathway. These findings suggested that ozone exposure could accelerate diabetic nephropathy progression by reshaping the systemic immune landscape. Notably, DAPA and YSHS, especially their combination, showed the potential to mitigate kidney injury by ozone through synergistically restoring glucose homeostasis, Th17/Treg balance and RORγt/IL-17 signaling to suppress systemic and local inflammation. This study provided valuable insights into the nephrotoxic effects associated with ozone exposure, and offered a reference for the development of intervention strategies targeting pollutant-driven metabolic kidney disease and the formulation of environmental regulations.