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.
There is no cure for polycystic kidney disease (PKD), and once kidney damage starts to occur, there is a universal decline in kidney function leading to end stage kidney disease. Some PKD patient loses their kidney function rapidly compared to others, but the exact reason is unknown. A high protein diet or unilateral nephrectomy (removing one kidney) increases kidney size (renal hypertrophy) and accelerates cyst growth in PKD. We found that a group of blood cells that protects us from fighting infection, called macrophages, were activated in PKD mouse after unilateral nephrectomy. This grant will determine whether a high protein diet and UNx have common mechanism that leads to severe cystic kidneys focusing on kidney macrophage activation. We will explore if there are any changes in gene expression in the kidney from this hypertrophic signaling and determine if any of these genes can be detected in the urine which can potentially serve as a biomarker.