The CCN family member 2 (CCN2, also known as connective tissue growth factor) may behave as a risk biomarker and a potential therapeutic target for renal disease. CCN2 participates in the regulation of inflammation and fibrosis. TGF-βis considered the main fibrogenic cytokine; however, in some pathological settings TGF-βalso has anti-inflammatory properties. CCN2 has been proposed as a downstream profibrotic mediator of TGF-β, but data on TGF-βrole in CCN2 actions are scarce. Our aim was to evaluate the effect of TGF-βblockade in CCN2-mediated experimental renal damage. Systemic administration of the C-terminal module of CCN2 to mice caused sustained renal inflammation. In these mice, TGF-βblockade, using an anti-TGF-βneutralizing antibody, significantly increased renal expression of the NGAL (a kidney injury biomarker), kidney infiltration by monocytes/macrophages, and upregulation of MCP-1 expression. The anti-inflammatory effect of TGF-βseems to be mediated by a dysregulation of the systemic Treg immune response, shown by decreased levels of circulating CD4⁺/Foxp3⁺Treg cells. Our experimental data support the idea that TGF-βexerts anti-inflammatory actions in the kidney and suggest that it is not an optimal therapeutic target.