Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

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.