Objective To investigate the effects of cyclic adenosine monophosphate (cAMP) signal of podocytes on expressions of podocyte marker protein Podocalyxin, chloride intracellular channel protein 5 (CLIC5), and relevant ezrin/radixin/moesin (ERM). Methods The adriamycin (ADR) nephrosis mouse model was established and some mice were treated by adenylate cyclase activator Forskolin (the ADR group and ADR+Forskolin group). Urinary protein levels were detected by the coomasie blue staining. The width of foot processes was observed under the electron microscope. The expressions of phosphorylated ERM (P-ERM), CLIC5, and Podocalyxin of podocytes were detected by the immunofluorescence staining and Western blotting. Results Compared to the ADR group, the urinary albumin level of the ADR+Forskolin group was significantly lower and the width of foot processes was significantly smaller (P<0.05). The results of immunofluorescence staining and Western blotting showed that compared to the ADR group, expressions and colocalization of P-ERM, Podocalyxin, and CLIC5 protein of podocytes of the ADR+Forskolin group significantly increased. The results of Western blotting showed that expressions of P-ERM and CLIC5 of podocytes significantly decreased after being cultured by puromycin aminonucleoside (PAN) for 72h in vitro (P<0.01). Pretreatment by Epac signal agonist 2Me-cAMP could prevent the low expression of P-ERM of podocytes induced by PAN, while pretreatment by PKA signal agonist pCPT-cAMP could prevent the low expression of CLIC5 induced by PAN. Conclusion Forskolin can alleviate albuminurine, widening of foot process, and low expression of Podocalyxin/ CLIC5/ERM protein complex of mice with nephrosis. And cAMP can prevent PAN-induced low expressions of CLIC5 and P-ERM through PKA and Epac signaling pathways, respectively.