Objective To explore the effect of chronic hypoxia on the proliferation and differentiation of LLCPK, cells. Methods: The cells were exposed either to hypoxia (3 % O2) or maintained in normoxia (18 % O2 )followed by the assessment of [3H]-thymidine incorporation and cell number as indices of cellular proliferation and sodium - dependent transport of glucose and aminoisobutyric acid (AIB) as indices of differentiation.Protein kinase C (PKC ) was determined with radionuclear technique. Results: Exposure of quiescent culturesto hypoxia for 16 h resulted in a significant increase in [3H]-thymldine followed by a significant increase incell number at 24 h in comparison with respective normoxic controls. Confluent cultures exposed to 72 h ofhypoxia exhibited significant inhibition of α--methyl glucose and AIB uptakes when compared with their respective norrnoxic counterparts. Hypoxia also activated PKC at 4 h followed by a subsequent return to baseline with reactivation at 24 h which remained sustained up to 72 h, suggesting a biphasic acute and sustainedactivation of PKC. Furthermore, the hypoxia--induced alterations in [H]-thymidine incorporation as well asα-methyl glucose and AId transport activities were mitigated by inhibitors of PKC. Conclusion: Chronic hypoxia induces both proliferation and dedifferentiation of LLC-PK, cells mediated, in part, by the sustained activation of PKC. Objective To explore the effect of chronic hypoxia on the proliferation and differentiation of LLCPK, cells. Methods: The cells were exposed either to hypoxia (3% O2) or maintained in normoxia (18% O2) followed by the assessment of [3H] thymidine incorporation and cell number as indices of cellular proliferation and sodium - dependent transport of glucose and aminoisobutyric acid (AIB) as indices of differentiation. Protein kinase C (PKC) was determined with radionuclear technique. Results: Exposure of quiescent culture sto hypoxia for 16 h resulted in a significant increase in [3H] -thymldine followed by a significant increase in cell number at 24 h in comparison with normoxic controls. Confluent cultures exposed to 72 h of hypoxia exhibited significant inhibition of α - methyl glucose and AIB uptakes when compared with their respective norrnoxic counterparts. Hypoxia also activated PKC at 4 h followed by a subsequent return to baseline with reactivation at 24 h which remaine d sustained up to 72 h, suggesting a biphasic acute and sustained activation of PKC. Furthermore, the hypoxia-induced alterations in [H] -thymidine incorporation as well as a-methyl glucose and AId transport activities were mitigated by inhibitors of PKC. Conclusion: Chronic hypoxia induces both proliferation and dedifferentiation of LLC-PK, cells mediated, in part, by the sustained activation of PKC.