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