Effects of PPAR agonists on proliferation and differentiation in human urothelium

TY - JOUR

T1 - Effects of PPAR agonists on proliferation and differentiation in human urothelium

AU - Varley, Claire L.

AU - Southgate, Jennifer

PY - 2008/9/18

Y1 - 2008/9/18

N2 - Systemic treatment of rats with peroxisome proliferator-activated receptor (PPAR) agonists (mainly of dual alpha/gamma activity) has indicated that they may invoke non-genotoxic carcinogenesis in the epithelial lining of the urinary tract (urothelium). Although there is evidence in the mate rat to support an indirect effect via a crystaluria-induced urothelial damage response, there is other evidence to indicate a direct signalling effect on the urothelium and hence the full implication for using these drugs in man is unclear. Numerous reports have demonstrated that PPARs are expressed within the urothelium of different species, including man, and from an early developmental stage. We have developed methods to maintain normal human urothelial (NHU) cells in culture, where the cells retain PPAR expression and express a highly proliferative phenotype, mediated via autocrine stimulation of the epidermal growth factor (EGF) receptor. We have shown that specific activation of PPAR gamma results in a programme of gene expression changes associated with late/terminal cytodifferentiation, including induction of cytokeratins CK13 and CK20, tight junction-associated claudin 3, and uroplakins UPK1a and UPK2, but this is dependent upon inhibition of the signalling cascade downstream of the EGF receptor. This indicates a subtle balance in the regulation of proliferation and differentiation in urothelium, with PPAR gamma agonists promoting differentiation. Our data indicate that human urothellum is a target tissue for PPAR gamma signalling, but it has yet to be determined whether dual agonists could have a modulatory effect on the proliferation/differentiation balance. (C) 2008 Elsevier GmbH. All rights reserved.

AB - Systemic treatment of rats with peroxisome proliferator-activated receptor (PPAR) agonists (mainly of dual alpha/gamma activity) has indicated that they may invoke non-genotoxic carcinogenesis in the epithelial lining of the urinary tract (urothelium). Although there is evidence in the mate rat to support an indirect effect via a crystaluria-induced urothelial damage response, there is other evidence to indicate a direct signalling effect on the urothelium and hence the full implication for using these drugs in man is unclear. Numerous reports have demonstrated that PPARs are expressed within the urothelium of different species, including man, and from an early developmental stage. We have developed methods to maintain normal human urothelial (NHU) cells in culture, where the cells retain PPAR expression and express a highly proliferative phenotype, mediated via autocrine stimulation of the epidermal growth factor (EGF) receptor. We have shown that specific activation of PPAR gamma results in a programme of gene expression changes associated with late/terminal cytodifferentiation, including induction of cytokeratins CK13 and CK20, tight junction-associated claudin 3, and uroplakins UPK1a and UPK2, but this is dependent upon inhibition of the signalling cascade downstream of the EGF receptor. This indicates a subtle balance in the regulation of proliferation and differentiation in urothelium, with PPAR gamma agonists promoting differentiation. Our data indicate that human urothellum is a target tissue for PPAR gamma signalling, but it has yet to be determined whether dual agonists could have a modulatory effect on the proliferation/differentiation balance. (C) 2008 Elsevier GmbH. All rights reserved.

KW - peroxisome proliferator-activated receptor

KW - differentiation

KW - proliferation

KW - epidermal growth factor

KW - bladder

KW - urothelium

KW - uroplakin

KW - claudin

KW - ACTIVATED RECEPTOR-GAMMA

KW - UROPLAKIN GENE-EXPRESSION

KW - CELLS IN-VITRO

KW - URINARY-BLADDER

KW - MEMBRANE-PROTEINS

KW - TIGHT JUNCTION

KW - MALE RATS

KW - MURAGLITAZAR

KW - LIGANDS

KW - DISEASE

UR - http://www.scopus.com/inward/record.url?scp=49949091267&partnerID=8YFLogxK

U2 - 10.1016/j.etp.2008.04.009

DO - 10.1016/j.etp.2008.04.009

M3 - Article

C2 - 18571911

SN - 0940-2993

VL - 60

SP - 435

EP - 441

JO - Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie

JF - Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie

IS - 6

ER -