Targeted deletion of angiotensin II type 1A receptor does not protect mice from progressive nephropathy of overload proteinuria.
In experimental and human renal diseases, progression is limited by angiotensin-converting enzyme inhibitors. Whether renoprotection was due to their capacity of reducing proinflammatory and profibrotic effects of angiotensin II (Ang II) or limiting proteinuria and its long term toxicity is debated. For dissecting the relative contribution of Ang II and proteinuria to chronic renal damage, the protein-overload proteinuria model was used in genetically modified mice lacking the major isoform of murine AT1 receptor (AT1A). Uninephrectomized AT1A+/+ and -/- mice received a daily injection of BSA or saline for 4 or 11 wk. AT1A-/-BSA mice acquired a renal phenotype of proteinuria and renal glomerular and tubulointerstitial lesions, albeit attenuated with respect to AT1A+/+BSA. Administration of the calcium channel blocker lacidipine to reduce BP of AT1A+/+BSA mice to levels of AT1A-/-BSA translated into comparable values of protein excretion rate and glomerular and tubulointerstitial injury in both strains. These results confirm that the toxic effect of protein trafficking on renal disease progression is not necessarily dependent on Ang II to the extent that targeted deletion of AT1A does not prevent disease progression. A role of Ang II via AT1B or AT2 receptors is still a possibility that cannot be ruled out by the present experimental approach. These findings provide a clear rationale for specifically targeting proteinuria in pharmacologic interventions of chronic nephropathies.
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. abenigni@marionegri.it
Ariela
A
Benigni
Daniela
D
Corna
Carla
C
Zoja
Lorena
L
Longaretti
Elena
E
Gagliardini
Norberto
N
Perico
Thomas M
TM
Coffman
Giuseppe
G
Remuzzi
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D018450:Disease Progression; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010784:Photomicrography; D011336:Probability; D011507:Proteinuria / Q000188:drug therapy* / Q000473:pathology; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D044139:Receptor, Angiotensin, Type 2