AIM:To determine the temporal expression and pattern of Rel/nuclear factor(NF)-κB proteins in renal tissue in polycystic kidney disease(PKD). METHODS: The renal expression of Rel/NF-κB proteins was determined by imm...AIM:To determine the temporal expression and pattern of Rel/nuclear factor(NF)-κB proteins in renal tissue in polycystic kidney disease(PKD). METHODS: The renal expression of Rel/NF-κB proteins was determined by immunohistochemistry, immunofluorescence and immunoblot analysis in Lewis polycystic kidney rats(LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mR NA expression of NF-κB-dependent genes(TNFa and CCL2) were determined. NF-κB was also histologicaly assessed in human PKD tissue.RESULTS: Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation(peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis(with a smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-κB proteins(phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells(CECs) of LPK kidneys as early as postnatal week 3 and sustained until latestage disease at week 20. From weeks 10 to 20, nuclear p65, p50, Rel B and cytoplasmic IκBa protein levels, and TNFa and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-κB proteins were consistently expressed in CECs of human PKD. The DNA damage marker γ-H2AX was also identified in the CECs of LPK and human polycystic kidneys. CONCLUSION: Several NF-κB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF-κB signaling may be a constitutive and early pathological feature of cystic renal diseases.展开更多
基金Supported by Funding from the National Health and Medical Research Council of Australia,Nos.457575 and 632647 to Rangan GKthe Baltimore Polycystic Kidney Disease Research and Clinical Core Center,No.P30DK090868+2 种基金DK095036 to Watnick Tsupported by an Australian Postgraduate Award(University of Sydney)the Michael Stern Polycystic Kidney Disease Research Fellowship
文摘AIM:To determine the temporal expression and pattern of Rel/nuclear factor(NF)-κB proteins in renal tissue in polycystic kidney disease(PKD). METHODS: The renal expression of Rel/NF-κB proteins was determined by immunohistochemistry, immunofluorescence and immunoblot analysis in Lewis polycystic kidney rats(LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mR NA expression of NF-κB-dependent genes(TNFa and CCL2) were determined. NF-κB was also histologicaly assessed in human PKD tissue.RESULTS: Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation(peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis(with a smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-κB proteins(phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells(CECs) of LPK kidneys as early as postnatal week 3 and sustained until latestage disease at week 20. From weeks 10 to 20, nuclear p65, p50, Rel B and cytoplasmic IκBa protein levels, and TNFa and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-κB proteins were consistently expressed in CECs of human PKD. The DNA damage marker γ-H2AX was also identified in the CECs of LPK and human polycystic kidneys. CONCLUSION: Several NF-κB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF-κB signaling may be a constitutive and early pathological feature of cystic renal diseases.