Dehydration Accelerates Cytogenesis and Cyst Growth in Pkd1Mice by Regulating Macrophage M2 Polarization.

Abstract

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 Pkd1mice by regulating macrophage activation. First, we confirmed that dehydration accelerated cytogenesis in Pkd1mice 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 Pkd1kidneys under conditions of dehydration. Further, we confirmed glycolysis pathway was activated and lactic acid (L-LA) was overproduced in the Pkd1kidney 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 Pkd1mice recurrently exposed to dehydration.