Abstract Objective To investigate the expression and distribution of podocin and its role in the development of proteinuria in rats with puromycin aminonucleoside (PAN) nephropathy. Methods The nephropathy model was established by a single injection of PAN. The rats in the Model group were sacrificed on days 1, 3, 10 and 20 after PAN injection. The renal histological changes were observed under light and electron microscopes. The indirect immunofluorescence staining and semiquantitative reverse transcription PCR were used to detect the expression of podocin. Six rats which received normal saline with the same volume as the Model group served as the Control group. Results ① The proteinuria which was gradually increased 3 days after PAN injection reached a peak on day 10 (P< 0.01) and decreased on day 20 but was still greater than that of the Control group (P< 0.05). ② In the process of development of PAN nephropathy, the foot process effacement was seen between 3 and 10 days following PAN injection. ③ The podocin expression began to decrease on day 1, and prominently decreased on day 3 and day 10 compared with those of the Control group (P< 0.01). On day 20, the podocin expression resembled that of day 1, remaining lower than that of the Control group (P< 0.05) although it partly retrieved with the decreased proteinuria. The podocin expression was negatively correlated with proteinuria (r= -0.786, P< 0.05). ④ Podocin staining showed a very fine linear-like pattern along the capillary loop in the Control group. It presented a discontinuous pattern on day 1, a granular pattern on day 3, more coarse granular on day 10 and gradually recovered to a linear-like pattern on day 20. ⑤ Podocin mRNA expression levels were slightly elevated on days 1, 3 and 10 ( 1.2, 1.5, 1.4 folds as the Control group respectively) and recovered to a normal level on day 20 compared with those of the Control group. Conclusions Podocin may be involved in the development of proteinuria and it may be a useful early marker of podocyte injury in nephropathy.