Smoking induces glomerulosclerosis in aging estrogen-deficient mice through cross-talk between TGF-beta1 and IGF-I signaling pathways.
Smoking is a known risk factor for the progression of chronic kidney diseases. However, its independent contribution to the development of ESRD and the underlying molecular mechanism have not been well elucidated. Although the risk for ESRD is higher in postmenopausal women according to the US Renal Data System, the number of women who smoke is on the rise worldwide. Therefore, the effects of smoking and estrogen status on glomerular function and structure were studied in female B6 mice that were ovariectomized at 3 (young) and 15 mo (aged) of age. The mice received either 17beta-estradiol (E(2)) replacement or placebo (Pla) and were divided further into groups that were exposed to cigarette smoke (S) and not exposed (NS). Six months of exposure to smoke had no effect on young mice, although aging S/Pla mice exhibited a phenotype of increased albumin excretion associated with a moderately increased glomerular collagen type IV deposition compared with NS/Pla mice. S/Pla mice also had a two-fold increase in glomerular TGF-beta, Smad3, and IGF-I receptor mRNA expression compared with the NS group. Mesangial cells that were isolated from S/Pla mice had an increase of IGF-I receptor protein, and IGF-I stimulated a TGF-beta reporter construct promoter three-fold. This was blocked by pretreatment with a neutralizing antibody to IGF-I, LY294002 (phosphatidylinositol-3 kinase inhibitor) or a dominant negative Smad construct. In addition, Smad3 activation was stimulated by IGF-I and blocked by LY294002, suggesting cross-talk between Smad and the phosphatidylinositol-3 kinase/AKT pathways. The smoking phenotype was reversed by E(2) replacement. In conclusion, smoking induces a phenotype in E(2)-deficient mice that is characterized by activation and cross-talk between the TGF-beta1 and IGF-I signaling pathways.
Elliot
Sharon J
SJ
Division of Nephrology, Miller School of Medicine, University of Miami Medical School, Miami, Florida 33136, USA. selliot@med.miami.edu
Karl
Michael
M
Berho
Mariana
M
Xia
Xiaomei
X
Pereria-Simon
Simone
S
Espinosa-Heidmann
Diego
D
Striker
Gary E
GE
D000375:Aging / Q000502:physiology; D000419:Albuminuria; D000818:Animals; D001835:Body Weight; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D004958:Estradiol / Q000172:deficiency / Q000494:pharmacology*; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology; D007676:Kidney Failure, Chronic / Q000209:etiology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D024141:Collagen Type IV; D007797:Laminin; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D053773:Transforming Growth Factor beta1; D004958:Estradiol; D003404:Creatinine