Reversible angiotensin II-mediated albuminuria in rat kidneys is dynamically associated with cytoskeletal organization.
Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exist at a normal physiological range of 6-10 nM within the renal tubules. The potential role that intrarenal ANG II may play in renal disease was assessed by perfusing isolated rat kidneys with or without excess intratubular levels of ANG II, which may mimic changes in the intrarenal RAS under pathological conditions. The effects of increased systemic ANG II were also determined by infusing rats with ANG II by osmotic pump. In isolated perfused kidneys, ANG II significantly and specifically increased the fractional clearance of albumin to clinical levels, as determined by using radiolabelled albumin. This effect was reversible, as removing ANG II from the perfusate caused the albumin fractional clearance to decrease to pre-ANG II exposure levels. The increase in fractional clearance of albumin was not correlated with renal hemodynamic changes, nor glomerular permeability alterations as measured by the fractional clearance of 36 A Ficoll and immunoglobulin G. Immunochemical analysis using anti-alpha-tubulin antibody of perfused kidney sections revealed that ANG II caused a marked disruption of tubular epithelial cytoskeletal components, through disassembly and reorganization of alpha-tubulin. This disruption was reversible. In vivo, osmotic pump delivery of ANG II at less potent dosage caused a proteinuria (Biuret) and an albuminuria (radioimmunoassay) in rats, from as early as 2 days after pump implantation. These results demonstrate that ANG II may reversibly induce clinical levels of albuminuria. These data point to an important role for renal tubules and the intratubular lumen concentrations of ANG II in the renal processing of albumin.
Clavant
Steven P
SP
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.
Forbes
Josephine M
JM
Thallas
Vicki
V
Osicka
Tanya M
TM
Jerums
George
G
Comper
Wayne D
WD
D000419:Albuminuria / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000652:urine; D000804:Angiotensin II / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001798:Blood Proteins / Q000652:urine; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D007150:Immunohistochemistry; D007260:Infusion Pumps; D007668:Kidney / Q000503:physiopathology; D007684:Kidney Tubules / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D007700:Kinetics; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000032:analysis / Q000276:immunology
D001798:Blood Proteins; D014404:Tubulin; D000804:Angiotensin II