Impact of Phosphaturia on Renal Osteopontin Production and PKD Progression

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PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (PKD) is characterized by the accumulation of numerous renal cysts leading to a progressive decline in kidney function, and frequently culminates in end-stage renal disease (ESRD). Aberrant tubular epithelial cell proliferation, macrophage infiltration, and tubulointerstitial fibrosis are important contributors to PKD progression; however, factors promoting these events remain undetermined. Systemic phosphate balance is tightly regulated, with renal excretion of phosphate being critically important for the elimination of excess dietary phosphate. When functional nephron numbers are reduced, as in PKD, phosphate excretion by residual nephrons is dramatically increased to preserve phosphate balance. Fibroblast growth factor 23 (FGF23), a circulating hormone that induces urinary phosphate excretion, is elevated in early- stage PKD. Both high dietary phosphate consumption and elevated FGF23 are associated with a more rapid decline in renal function in chronic kidney disease (CKD), indicating that increased urinary phosphate excretion may contribute to decrements in kidney function. We propose that high concentrations of tubular phosphate are nephrotoxic, leading to progressive renal injury, immune cell infiltration, and fibrosis. In preliminary studies, we observed two phosphaturic mouse models (NaPi2a-/- and Hyp mice) to exhibit increased renal gene expression for markers of early kidney injury and fibrosis. Moreover, additional experiments revealed dietary phosphate restriction to slow PKD progression in pcy/pcy mice. Osteopontin (OPN), a matricellular protein that uses an ASARM peptide motif to enhance phosphate solubility in urine, is increased by tubular epithelial cells in PKD. OPN has established functions to stimulate cell proliferation and enhance macrophage recruitment to sites of cellular injury; thus, renal OPN production in PKD may contribute to the pathophysiology of cystic kidney disease. We hypothesize that high concentrations of tubular phosphate in PKD contribute to epithelial cell injury and OPN production, which together promote cyst epithelial cell proliferation and macrophage recruitment that accelerate kidney disease progression. We will use cell culture and mouse studies to determine: (1) the impact of high urine phosphate on PKD progression, (2) the role of osteopontin in cyst epithelial cell proliferation, macrophage recruitment and interstitial fibrosis, and (3) if administration of an ASARM peptide can enhance the solubility of tubular phosphate and prevent PKD progression.