TNF-alpha (TNF-?) is considered to be a critical effector cytokine in autosomal dominant polycystic kidney disease (ADPKD), and anti-TNF-? therapy or targeting TNF-? dependent signaling pathway has emerged to have high efficacy in the treatment of this disease. TNF-? has been shown to stimulate macrophage migration inhibitory factor (MIF) mRNA expression and protein secretion whereas MIF also acts as an important upstream regulator of TNF-? expression. The close relationship between TNF-? and MIF provides a rationale for us to investigate the functional roles of MIF in ADPKD. MIF regulates the cellular activities through transcriptional regulation of inflammatory gene products, modulation of cell proliferation, differentiation and metabolism, and inhibition of apoptosis, and its cell surface receptor CD74 is involved in these processes. MIF also induces macrophage recruitment to sites of inflammation through MCP-1. The proteins and pathways regulated by MIF and CD74 include Src, ERK, mTOR, AMPK, Rb, Akt, and p53 as well as TNF-? and MCP-1 in different cell types. Notably, all the proteins and pathways listed are hyperactive in PKD. We found that the expression of MIF and CD74 was upregulated in cystic renal epithelial cells and tissues and targeting MIF with its inhibitor ISO-1, 1) decreases cyst-lining epithelial cell proliferation; 2) induces cyst-lining epithelial cell apoptosis; 3) reduces the recruitment of macrophages at the regions surrounding cyst and interstitium; 4) decreases interstitial fibrosis; and most importantly, 5) delays cyst growth and preserved renal function in three genetic strains of mice with Pkd1 mutations. MIF may regulate these processes via CD74. However, in addition to be a cell membrane receptor of MIF, CD74 by itself is a multifunctional protein and is considered a therapeutic target in malignancy. So far, there is only limited experimental data on CD74 targeting in kidney disease and in renal fibrosis. Our central hypothesis is that upregulation of MIF and CD74, either alone or together, regulates cyst growth and interstitial fibrosis in Pkd1 knockout mouse kidneys. We propose three specific aims to test this hypothesis.
Aim 1. Determine if targeting MIF delays cyst growth and decreases interstitial fibrosis in a milder inducible Pkd1 conditional knockout mice and investigate the mechanisms for the upregulation of MIF in PKD.
Aim 2. Determine if genetic loss or inhibition of CD74 slows cyst progression and decreases interstitial fibrosis in kidneys from Pkd1 mutant mice.
Aim 3. Determine the roles and mechanisms of MIF and CD74 in regulation of renal interstitial fibrosis. Accomplishing this study will elucidate the roles of MIF and CD74 as key and novel upstream regulators of cyst formation and interstitial fibrosis, and will determine if MIF and CD74 are novel therapeutic targets to slow disease progression in clinical setting. In sum, this study will lead to a better understanding of the genetic and pathological mechanisms of renal cyst formation and has a direct potential to accelerate the development of potential therapies.
In this study, we will investigate the functional roles of macrophage migration inhibitory factor (MIF) in regulating cystic epithelial cell proliferation, apoptosis glucose uptake and interstitial fibrosis through its receptor CD74 mediated signaling pathways and regulates macrophage recruitment through MCP-1 in Pkd1 knockout mouse kidneys. Accomplishing this study will elucidate the roles of MIF and CD74 as key and novel upstream regulators of cyst formation and will identify the key regulatory components that may serve as effective targets to slow disease progression in clinical setting. Thus, this is a highly significant renewal proposal which will lead to a better understanding of the mechanism of renal cyst formation and will provide a novel therapeutic target(s) for ADPKD.
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