Obesity and nonalcoholic fatty liver disease (NAFLD) are associated with the development and progression of chronic kidney disease. We recently showed that NAFLD induces liver specific CYP2E1-mediated metabolic oxidative stress following administration of a CYP2E1 substrate bromodichloromethane (BDCM). The present study examined the effects of CYP2E1 mediated oxidative stress in NAFLD leading to kidney toxicity. Mice were fed a high fat diet for 12 weeks to induce NAFLD. NAFLD mice were exposed to BDCM, a CYP2E1 substrate for 4 weeks. NAFLD+BDCM increased CYP2E1-mediated lipid peroxidation in proximal tubular cells compared to mice with NAFLD alone or BDCM -treated lean mice thus ruling out the exclusive role of BDCM. The lipid peroxidation increased IL1β, TNFα and IFN-. In parallel mesangial cell activation was observed by increased α-SMA and TGF-β, which was blocked by the CYP2E1 inhibitor Diallyl sulphide (DAS) both in vivo and in vitro Mice lacking NKT cells (CD1d KO) showed elevated (>4-fold) pro-inflammatory mediator release, increased TLR4 and PDGF2 mRNA and mesangial cell activation in the kidney. Finally, NAFLD-CD1D KO mice treated with BDCM exhibited increased HMGB1, FasL levels, and TUNEL positive nuclei indicating higher cell death that was attenuated in TLR4 KO mice. Tubular cells showed increased cell death and cytokine release when incubated with activated mesangial cells. In summary, an underlying condition of progressive NAFLD causes renal immunotoxicity and aberrant glomerular function possibly through HMGB1-dependent TLR4 signaling and mesangial cell activation which in turn is modulated by intrinsic CD1D dependent NKT cells.