Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease, with the predominant form resulting from mutations in the gene, PKD1. In ADPKD, cyst expansion/tubular dilation leads to a loss of nephrons and eventually to kidney failure. There are significant subset of ADPKD patients that develop severe accelerated cystic disease leading to end stage renal disease earlier in life. Accelerated cystogenesis may be due, in part, to the effects of “modifying factors” a group of conditions that triggers a phenotypic switch from slow to rapid cystic growth when superimposed on PKD. We have provided compelling evidence that hypertrophic signaling is a critical modifier that stimulates rapid cystic disease progression. Unilateral nephrectomy (UNx) and protein load both stimulates glomerular hyperfiltration and promotes rapid cystic growth in mouse models of PKD. Interestingly, children with PKD that exhibit glomerular hyperfiltration were shown to have a higher rate of cyst growth and faster decline in kidney function. Protein load/restriction in murine models of PKD have been shown to promote/slow cystogenesis. Despite evidence of renal hypertrophy accelerating cystogenesis, there is a gap in our knowledge of how hypertrophic signaling leads to rapid cyst growth. Our new data from RNA-seq of kidney tissue comparing UNx to intact kidney from a sham operated Pkd1 knockout mice, show differentially expressed genes involved in activating/recruiting macrophages and production of pro-inflammatory cytokines during the hypertrophic signaling. We also show preliminary results that high protein diet significantly increases kidney weight/cystogenesis in adult Pkd1 mice. This proposal will determine whether conditions which trigger renal hypertrophy (both UNx and protein load), activate kidney (resident) macrophages and leads to accelerated cyst growth in adult PKD mice. We will also begin to examine potential biomarkers linked to rapid cystic progression with a focus of identifying individuals at risk for accelerated cystogenesis.