Distinct roles of Mac-1 and its counter-receptors in neonatal obstructive nephropathy.
Urinary tract obstruction during renal development leads to tubular atrophy and interstitial fibrosis. Inflammatory macrophages are crucial in this process, and beta2-integrins play a major role in leukocyte recruitment. We investigated the role of beta2-integrins and their major counter-receptors (intercellular adhesion molecule-1 (ICAM-1), receptor for advanced glycation endproducts (RAGE), junctional adhesion molecule (JAM)-C) in obstructive nephropathy in neonatal mice. Two-day-old beta2-integrin-deficient mice (Mac-1-/- and LFA-1-/-(deficient for leukocyte function-associated antigen-1)) and wild-type mice (C57BL/6) underwent unilateral ureteral obstruction (UUO) or sham operation. After 1, 5 or 12 days of obstruction, renal macrophage infiltration and tubulointerstitial damage were quantitated. Tissue abundance of Mac-1 and its ligands ICAM-1, RAGE and JAM-C was examined by Western blot and immunoprecipitation. Deficiency of either integrin was associated with reduced early macrophage invasion into the obstructed kidney. After 12 days of UUO, macrophage infiltration and tubulointerstitial injury were reduced only in Mac-1-/- but not in LFA-1-/- mice. Besides ICAM-1, an upregulation of two novel Mac-1 ligands, RAGE and JAM-C were observed, however, with distinct time courses. We conclude that beta2-integrins mediate macrophage infiltration in UUO. Mac-1 is the predominant leukocyte integrin involved in leukocyte recruitment after obstruction. ICAM-1 and its new ligands RAGE and JAM-C are sequentially activated in UUO. Blocking of Mac-1 and its ligands may confer synergistic renoprotective effects in neonatal obstructive nephropathy.
Lange-Sperandio
B
B
Department of Pediatrics, University of Heidelberg, Heidelberg, Germany. baerbel.lange-sperandio@med.uni-heidelberg.de
Schimpgen
K
K
Rodenbeck
B
B
Chavakis
T
T
Bierhaus
A
A
Nawroth
P
P
Thornhill
B
B
Schaefer
F
F
Chevalier
R L
RL
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000502:physiology*; D005260:Female; D005355:Fibrosis; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D062726:Junctional Adhesion Molecules; D007668:Kidney / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D014517:Ureteral Obstruction / Q000473:pathology*
D015815:Cell Adhesion Molecules; D062726:Junctional Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018799:Intercellular Adhesion Molecule-1