The pathological features of diabetic nephropathy(DN)include glomerulosclerosis, thickening of the glomerular basement membrane, glomerular hypertrophy, mesangial cell expansion, podocyte loss, renal-cell hypertrophy and tubulointerstitial fibrosis. Recent studies have demonstrated the loss of podocyte is a critical event in DN. Many studies suggested that DN podocyte injury was induced by the association of multiple factors, including mechanical stress, inflammatory reaction, oxidative stress, TGF-β1 induction, renin angiotensin aldosterone system (RAAS) activation, and AGEs accumulation. Previously, our group have found the mitotic arrest deficient protein MAD2B is implicated in high glucose (HG)-induced podocyte injury by regulating cell cycle. However, the exact mechanism of MAD2B in podocyte injury is lacking. Numb was originally discovered as an intrinsic cell fate determinant in Drosophila by antagonizing Notch signaling which may play a pivotal pathogenic role in podocyte injury. In vivo study, DN model was constructed on C57BL/6 mice by a single intra-peritoneal injection of STZ. Our group also successfully constructed gene knockout mice with podocyte-specific depletion of MAD2B (NMKO). In vitro study, immortalized human podocyte cell line was employed, and exposed to different treatments after differentiation. The expression of MAD2B and Numb was suppressed by recombinant lentivirus infection,while Numb was elevated by adenovirus infection. Our latest finding revealed that HG exposure downregulated Numb expression in podocytes and DN mice resulting in increase of NICD and Hes-1 and mitotic catastrophe of podocyte. In addition, the overexpression of Numb could alleviate podocyte injury through decreasing the expression of Desmin and increasing autophagy. Previously we have demonstrated the enhancement of MAD2B in DN mice and HG treated podocytes. Interestingly, MAD2B genetic deletion could partly reverse the decline of Numb in podocytes when exposed to HG. Accordingly, the expressions of Numb downstream molecules such as NICD and Hes-1 were decreased. Afterwards we identified Numb as a novel MAD2B binding protein in human kidney through screens using a yeast two-hybrid interaction trap. Through confocal laser scanning microscopy we confirmed the co-localization of MAD2B and Numb in podocyte in vivo and in vitro. Subsequent endogenous co-immunoprecipitation established the direct interaction between MAD2B and Numb. The mechanisms of interaction between them still remains to be established. Upregulated MAD2B expression contributes to Numb depletion and its downstream protein accumulation such as NICD and Hes-1 in HG condition,which ultimately leads to podocyte mitosis abnormality and cell polarity disorder. However, inhibiting MAD2B expression could reverse podocyte injury by maintaining normal cell cycle and increasing autophagy.