title: Transforming growth factor-β1 receptor inhibition preserves glomerulotubular integrity during ureteral obstruction in adults but worsens injury in neonatal mice.
abstract: Unilateral ureteral obstruction (UUO), a widely used model of chronic kidney disease and congenital obstructive uropathy, causes proximal tubular injury and formation of atubular glomeruli. Because transforming growth factor-β1 (TGF-β1) is a central regulator of renal injury, neonatal and adult mice were subjected to complete UUO while under general anesthesia and treated with vehicle or ALK5 TGF-β1 receptor inhibitor (IN-1130, 30 mg·kg(-1)·day(-1)). After 14 days, glomerulotubular integrity and proximal tubular mass were determined by morphometry of Lotus tetragonolobus lectin distribution, and the fraction of atubular glomeruli was determined by serial section analysis of randomly selected individual glomeruli. Glomerular area, macrophage infiltration, fibronectin distribution, and interstitial collagen were measured by morphometry. Compared with placebo, inhibition of TGF-β1 by IN-1130 decreased apoptosis and formation of atubular glomeruli, prevented parenchymal loss, increased glomerular area and glomerulotubular integrity, and increased proximal tubule fraction of the adult obstructed kidney parenchyma from 17 to 30% (P < 0.05, respectively). IN-1130 decreased macrophage infiltration and fibronectin and collagen deposition in the adult obstructed kidney by ∼50% (P < 0.05, respectively). In contrast to these salutary effects in the adult, IN-1130 caused widespread necrosis in obstructed neonatal kidneys. We conclude that whereas IN-1130 reduces obstructive injury in adult kidneys through preservation of glomerulotubular integrity and proximal tubular mass, TGF-β1 inhibition aggravates obstructive injury in neonates. These results indicate that while caution is necessary in treating congenital uropathies, ALK5 inhibitors may prevent nephron loss due to adult kidney disease.
authors.affiliation: Dept. of Pediatrics, Univ. of Virginia, Box 800386, Charlottesville, VA 22908, USA.
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Galarreta
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Thornhill
authors.forename: Michael S
authors.initials: MS
authors.lastname: Forbes
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Simpkins
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.forename: Robert L
authors.initials: RL
authors.lastname: Chevalier
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000473:pathology
chemical_list: C530153:3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D007093:Imidazoles; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta