Regulatory T cells (T-regs) have been recognized as central mediators for maintaining peripheral tolerance and limiting autoimmune diseases. The loss of T-regs or their function has been associated with exacerbation of autoimmune disease. However, the temporary loss of T-regs in the chronic spontaneous disease model has not been investigated. In this study, we evaluated the role of T-regs in a novel chronic spontaneous glomerulonephritis model of B cell lymphoma 2-interacting mediator (Bim) knock-out mice by transient depleting T-regs. Bim is a pro-apoptotic member of the B cell lymphoma 2 (Bcl-2) family. Bim knock-out (Bim(-/-)) mice fail to delete autoreactive T cells in thymus, leading to chronic spontaneous autoimmune kidney disease. We found that T-reg depletion in Bim(-/-) mice exacerbated the kidney injury with increased proteinuria, impaired kidney function, weight loss and greater histological injury compared with wild-type mice. There was a significant increase in interstitial infiltrate of inflammatory cells, antibody deposition and tubular damage. Furthermore, the serum levels of cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17, interferon (IFN)- and tumour necrosis factor (TNF)- were increased significantly after T-reg depletion in Bim(-/-) mice. This study demonstrates that transient depletion of T-regs leads to enhanced self-reactive T effector cell function followed by exacerbation of kidney disease in the chronic spontaneous kidney disease model of Bim-deficient mice.