Dysregulated growth factor gene expression is associated with tubulointerstitial apoptosis and renal dysfunction.
Chronic renal disease is characterized by declining renal function, loss of intrinsic renal cells, and their replacement with fibrotic tissue. This study investigates apoptosis and its regulation in the context of chronic renal disease. RNA was extracted from renal biopsies from patients with various forms of chronic renal disease. Expression of genes of the Bcl-2 family, death receptor pathway, and growth factors were measured by reverse-transcription real-time polymerase chain reaction. Apoptosis was detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling technique. Tubulointerstitial apoptosis was positively associated with tubulointerstitial injury and renal dysfunction and increased 2.3-fold per unit (U) increase in transforming growth factor beta(1) (TGFbeta(1)) mRNA (P<0.05). Conversely, a 1 U increase in epidermal growth factor (EGF) mRNA was associated with a 47% decrease in tubulointerstitial apoptosis (P<0.05). Tubulointerstitial injury was correlated with increased TGFbeta(1) and tumour necrosis factor alpha (TNFalpha) mRNA (P<0.005) and decreased EGF mRNA (P<0.05). Additionally, for a 10 U decrease in the glomerular filtration rate there was an estimated increase of 5 and 10% in TGFbeta(1) and TNFalpha mRNA, respectively (P<0.05), whereas EGF mRNA decreased by an estimated 15% (P<0.005). Therefore dysregulation of cytokine/growth factor expression plays a central role in the progression of chronic renal disease through contribution to renal cell loss, tubulointerstitial injury, and renal dysfunction.
Teteris
S A
SA
Department of Medicine, Central and Eastern Clinical School, Monash University, Prahran, Victoria, Australia.
Menahem
S A
SA
Perry
G
G
Maguire
J A
JA
Dowling
J P
JP
Langham
R G
RG
Thomson
N M
NM
Stein
A N
AN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002908:Chronic Disease; D004815:Epidermal Growth Factor / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015415:Biomarkers; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor