title: Tissue transglutaminase and the progression of human renal scarring.
abstract: Experimental renal scarring indicates that tissue transglutaminase (tTg) may be associated with the accumulation of extracellular matrix (ECM), both indirectly via TGF-beta1 activation and directly by the formation of epsilon(gamma-glutamyl) lysine dipeptide bonds within the ECM. The latter potentially accelerates deposition and confers the ECM with resistance to proteolytic digestion. Studied were 136 human renal biopsy samples from a range of chronic renal diseases (CRD) to determine changes in tTg and epsilon(gamma-glutamyl) lysine crosslinking. Immunofluorescence for insoluble tTg showed a 14-fold increase in the kidneys of CRD patients (5.3 +/- 0.5 versus 76 +/- 54 mV/cm(2)), which was shown to be active by a similar 11-fold increase in the epsilon(gamma-glutamyl) lysine crosslink (1.8 +/- 0.2 versus 19.3 +/- 14.2 mV/cm(2)). Correlations were obtained with renal function for tTg and crosslink. In situ hybridization for tTg mRNA showed that tubular epithelial cells were the major source of tTg; however, both mesangial and interstitial cells also contributed to elevated levels in CRD. This mRNA pattern was consistent with immunohistochemistry for soluble tTg. Changes in renal tTg and its product, the epsilon(gamma-glutamyl) lysine crosslink, occur in progressive renal scarring in humans independently of the original etiology and in a similar manner to experimental models. tTg may therefore play a role in the pathogenesis of renal scarring and fibrosis in patients with CRD and can therefore be considered a potential therapeutic target.
authors.affiliation: Sheffield Kidney Institute, Sheffield, United Kingdom. T.Johnson@sheffield.ac.uk
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Johnson
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: El-Koraie
authors.forename: N James
authors.initials: NJ
authors.lastname: Skill
authors.forename: Nahed M
authors.initials: NM
authors.lastname: Baddour
authors.forename: A Meguid
authors.initials: AM
authors.lastname: El Nahas
authors.forename: Melvin
authors.initials: M
authors.lastname: Njloma
authors.forename: Ahmed G
authors.initials: AG
authors.lastname: Adam
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001706:Biopsy; D002921:Cicatrix / Q000473:pathology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases / Q000502:physiology*
chemical_list: D000906:Antibodies; D003432:Cross-Linking Reagents; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases; D008239:Lysine