Dehydration Accelerates Cytogenesis and Cyst Growth in Pkd1^−/− Mice by Regulating Macrophage M2 Polarization

Adult autosomal dominant polycystic kidney disease (ADPKD) has been shown to be related as a “third hit” to the occurrence of acute or chronic kidney injury. Here, we examined whether dehydration, as a common kidney risk factor, could cause cystogenesis in chronic-onset Pkd1^−/− mice by regulating macrophage activation. First, we confirmed that dehydration accelerated cytogenesis in Pkd1^−/− mice and that macrophages infiltrated the kidney tissues even earlier than macroscopic cyst formation. Then, microarray analysis suggested that glycolysis pathway may be involved in macrophage activation in Pkd1^−/− kidneys under conditions of dehydration. Further, we confirmed glycolysis pathway was activated and lactic acid (L-LA) was overproduced in the Pkd1^−/− kidney under conditions of dehydration. We have already proved that L-LA strongly stimulated M2 macrophage polarization and overproduction of polyamine in macrophage in vitro, and in the present study, we further discovered that M2 polarization-induced polyamine production shortened the primary cilia length by disrupting the PC1/PC2 complex. Finally, the activation of L-LA–arginase 1–polyamine pathway contributed to cystogenesis and progressive cyst growth in Pkd1^−/− mice recurrently exposed to dehydration.