Transforming growth factor-beta in acute renal failure: receptor expression, effects on proliferation, cellularity, and vascularization after recovery from injury.
Transforming growth factor (TGF)-beta1 and a number of TGF-beta-responsive genes are transiently enhanced following induction of ischemic acute renal failure (ARF) in the rat. The mRNA and protein expression of TGF-beta receptors were analyzed in postischemic rat kidneys by ribonuclease protection, in situ hybridization, and immunohistochemistry. TGF-betaRI and -RII were enhanced within 3 days of ischemia-reperfusion (I/R) injury and remained elevated for up 7 days post-I/R; TGF-beta receptor expression was localized primarily in regenerating tubules within the outer medulla. A neutralizing TGF-beta antibody exacerbated cellular proliferation observed on day 3 postischemia but had no effect on day 1 or 2. TGF-beta antibody treatment had no measurable effect on loss of renal function or the restoration of renal function during the recovery response for up to 35 days postsurgery. However, ischemic injury resulted in modest renal hypertrophy that is due, in part, to in an increase in the number of interstitial cells in the postischemic kidney. Immunohistochemistry showed that several of these cells stained positively for the fibroblast-specific marker, S100A4 positive. Anti-TGF-beta treatment substantially attenuated the renal hypertrophy, interstitial cellularity, and S100A4-positive cells present at 35 days post-I/R. Finally, TGF-beta immunoneutralization attenuated the loss of renal vascular density following recovery from I/R injury. These data suggest that the TGF-beta/TbetaR system is enhanced in the postischemic kidney. However, the current study failed to identify a prominent role for this system in the repair of proximal tubules following ARF. In contrast, the activation of this system may play an important role in the long-term structure of the postischemic kidney by influencing microvascular structure and interstitial cellularity.
Spurgeon
Kimberly R
KR
Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Donohoe
Deborah L
DL
Basile
David P
DP
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009500:Neutralization Tests; D023282:Nuclease Protection Assays; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D012079:Renal Circulation / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D009418:S100 Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D015415:Biomarkers; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C030564:S-100 calcium-binding protein alpha subunit; D009418:S100 Proteins; D016212:Transforming Growth Factor beta