[107] Immunohistochemistry localized p65 to CEC nuclei in Pkd1−/− kidney explants.[107] Similarly, Park et al. identified an unspecified phosphorylated NF-κB protein in CEC nuclei and in tubules surrounding the cysts of PKD2 mice and human ADPKD kidneys.[20]

Increased levels of phosphorylated and unphosphorylated NF-κB protein, and phosphorylated-IKKα/β were observed in PKD2 mice compared with wild-type mice, as well as increased levels of RAGE (receptor of advanced glycation end product, which is associated with renal inflammatory cell migration)[108] and s100a8 and s100a9 (inflammation-associated calcium binding proteins).[20, 109] In PKD2 mice, RAGE was located in CEC, and s100a8/a9 in CEC and interstitial areas proximate to inflammatory cells.[20] These data suggest that NF-κB activation is upregulated in human and animal models of PKD, and may be associated with increased inflammatory PD0325901 nmr mediators. Moreover, Qin et al. demonstrated that NF-κB inhibition modulated cystic disease, resulting in a three-fold decrease in histological cyst area.[107] NF-κB inhibition diminished the mRNA expression of three upregulated genes in PKD2 kidney explants: Wnt7a and Wnt7b, which are believed to be involved in polar cell polarity,[110] and Pax2, which is involved in embryonic nephron development.[107, 111, 112] NF-κB thus provides a promising

target for therapy, though further studies are required to characterize the effects, if any, of NF-κB on inflammation in PKD. Inflammation in PKD may be find more caused by abnormal regulation of the JAK-STAT pathway. Receptor binding of cytokines (e.g. IL-6 and interferon-γ), activates JAK proteins, which in turn activate STAT (signal transducer and activator of transcription) proteins, leading to gene transcription.[113] In vitro studies have shown that PC1 and PC2 are required for JAK1 and JAK2 activation,[114] and that Pkd1 regulates STAT3.[114] Therefore, Pkd1/2 mutations may promote inflammation by interrupting the control of JAK-STAT signalling. Furthermore, the JAK-STAT pathway is regulated by the suppressors of cytokine signalling (SOCS),[115] such as SOCS-1, which limits

the inflammatory activity of cytokines and macrophages.[116] Decitabine SOCS-1 knockout has led to the development of polycystic kidneys in mice,[117] but it is unknown whether this effect was mediated by inflammation or other facets of JAK-STAT signalling. Interstitial inflammation appears to correlate with disease progression in PKD. For example, heterozygous Han:SPRD rats display increased inflammatory cells at late stages of disease when there is severe interstitial fibrosis, proteinuria and extensive cystic expansion.[34] Given this, is it possible that inflammation induces cystogenesis? In some interventional studies, the amelioration of interstitial inflammation is accompanied by reduced cyst growth,[118, 119] though this does not prove causality.