Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide. The purpose of this study is to investigate whether Wld^S (slow Wallerian degeneration; also known as Wld) gene plays a renoprotective role during the progression of DN. Diabetes was induced in eight-week-old male wild-type (WT) and C57BL/WldS mice by streptozotocin (STZ) injection. Blood and urinary variables including blood glucose, glycated hemoglobin (GHb), insulin, urea nitrogen and albumin/creatinine ratio were assessed 4, 7 and 14 weeks after STZ injection. Periodic acid-Schiff (PAS) staining, Masson staining and silver staining were performed for renal pathological analyses. In addition, the renal ultrastructure was observed by electron microscope. The activities of p38 and ERK signaling in renal cortical tissues were evaluated by western blot. NAD⁺/NADH ratio and NADPH oxidase activity were also measured. Moreover, the expressions of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6 were examined. We provide experimental evidence demonstrating that the WldS gene is expressed in kidney cells and protects against early stage of diabetes-induced renal dysfunction and extracellular matrix accumulation through delaying the reduction of NAD⁺/NADH ratio, inhibiting the activation of p38 and ERK signaling and suppressing oxidative stress as evidenced by the decreased NADPH oxidase activity and lower expression of TNF-α, IL-1 and IL-6.