High Urinary Phosphate Induces TLR4-mediated Inflammation and Cystogenesis in Polycystic Kidney Disease

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the presence of numerous fluid-filled cysts, interstitial inflammation, and fibrosis leading to a progressive decline in kidney function. Emerging evidence suggests that urinary phosphate (Pi) promotes cystogenesis and activates innate immune responses. In previous studies, a high Pi diet was shown to increase renal CaPi nanocrystal deposition and accelerated cyst growth in a non-orthologous rodent model of ADPKD; whereas the restriction of dietary Pi attenuated disease progression. Relentless cyst growth in ADPKD leads to the loss of functional nephrons and compensatory hyperfiltration of unaffected nephrons increases single nephron Pi excretion to preserve Pi balance. Supersaturated intratubular Pi levels can lead to the formation of CaPi nanocrystals that cause tubule damage and inflammatory responses. Recently, toll-like receptor 4 (TLR4), a key component of innate immunity, has been suggested to mediate high urinary Pi-induced NF-κB activation and tubule damage; however, the role of TLR4 as the primary mediator in high Pi-induced PKD acceleration has not been studied. Resolvins, a family of endogenous lipid derivatives, cease innate immune responses after injury through inhibiting NF-κB and reduce renal mineral crystal deposition by increasing phagocytosis of macrophages. Currently, the therapeutic effects of resolvins have not been evaluated in PKD. In preliminary studies, human ADPKD kidneys have elevated crystal deposition and higher TLR4 expression in cystic lining cells compared with normal human kidneys. Incubation of human ADPKD cells with CaPi nanocrystals increased TNF-α mRNA suggesting CaPi nanocrystals stimulate TLR4/NF-κB signaling pathway. Challenging Pkd1RC/RC mice, an orthologous ADPKD model, with a high Pi diet accelerated cyst growth and increased injury, inflammation, and fibrosis markers. We also found that short-term administration of resolvin D1 reduced the renal expression of inflammation markers including TNF-α, IL-1β, and MCP-1, in Pkd1RC/RC mice. Thus, we hypothesized that high urinary Pi leads to TLR4/NF-κB- dependent innate immune responses in ADPKD, and that inhibition of NF-κB using resolvins attenuates disease progression. The proposed experiments will determine: (1) the role of TLR4 in mediating the effect of high dietary Pi on cystogenesis, and (2) if inhibiting innate immune response using resolvins can prevent PKD progression. The PI will work closely with the Office of the Vice President for Research and in coordination with the strategies led by the Vice President for Diversity and Inclusion to develop and implement a robust recruitment plan for diverse undergraduate students. The PI has tremendous enthusiasm and successful experience in training undergraduate and graduate students. This proposal will: (1) provide more opportunities for undergraduate students at Michigan Technological University to participate in Biomedical Research, (2) lay the groundwork for the PI’s future contributions to the fields of PKD, and (3) diversify university research infrastructure by introducing innate immunity and PKD.