Global Adam17 Deficiency Preserves Renal Function and Modulates Integrated Pathogenic Responses in Experimental Diabetic Kidney Disease

Diabetic kidney disease (DKD) progression results from complex interactions between metabolic stress, inflammatory activation, maladaptive intracellular signalling, and fibrotic remodelling. While previous studies demonstrated renoprotective effects of cell-specific Adam17 deletion, the impact of global Adam17 deficiency on the integrated renal response to diabetes remains incompletely understood. Here, we investigated the effects of tamoxifen-induced global Adam17 deletion in a streptozotocin-induced murine model of type 1 diabetes. Renal function, structural injury, inflammatory responses, stress-related signalling pathways, and fibrotic remodelling were comprehensively assessed in diabetic Adam17 knockout and control mice. Despite persistent hyperglycemia and ongoing albuminuria, diabetic Adam17 knockout mice exhibited preservation of glomerular filtration rate together with marked attenuation of diabetes-associated kidney injury. Global Adam17 deletion reduced mesangial expansion and structural damage, limited macrophage infiltration and chemokine expression, and significantly attenuated fibrotic remodelling. At the molecular level, Adam17 deficiency was associated with selective modulation of stress-related signalling pathways, including reduced activation of the PI3K/Akt axis and partial preservation of mitochondrial stress regulators, without evidence of generalized suppression of cellular stress responses. Notably, preservation of renal function occurred despite persistent albuminuria, supporting a partial dissociation between glomerular permeability alterations and progressive renal dysfunction. These findings demonstrate that global Adam17 deletion confers robust protection against diabetes-associated kidney injury through coordinated attenuation of inflammatory, stress-related, and profibrotic pathways. Our results extend previous cell-specific observations and highlight the context-dependent role of Adam17 in DKD progression, supporting the concept that integrated Adam17-related signalling may represent a relevant therapeutic target in diabetic kidney disease.