Intrarenal dopamine modulates progressive angiotensin II-mediated renal injury.
Authors Yang S, Yao B, Zhou Y, Yin H, Zhang MZ, Harris RC
Submitted By Raymond Harris on 8/1/2012
Status Published
Journal American journal of physiology. Renal physiology
Year 2012
Date Published 3/1/2012
Volume : Pages 302 : F742 - F749
PubMed Reference 22169008
Abstract It is well-recognized that excessive angiotensin II (ANG II) can mediate
progressive renal injury. Previous studies by us and others have indicated that
dopamine may modulate actions of ANG II in the kidney. The current studies
investigated whether altering intrarenal dopamine levels affected ANG
II-mediated renal fibrosis. We utilized a model of increased intrarenal
dopamine, catechol-O-methyl-transferase knockout (COMT KO) mice, which have
increased kidney dopamine levels due to deletion of a major intrarenal
dopamine-metabolizing enzyme. In wild-type mice, chronic ANG II infusion
increased renal expression of both of the major dopamine-metabolizing enzymes,
COMT and monoamine oxidase. After 8 wk of ANG II infusion, there were no
significant differences in blood pressure between wild-type and COMT KO mice.
Compared with wild-type, COMT KO mice had decreased albuminuria and
tubulointerstitial injury. In response to ANG II infusion, there was decreased
expression of both glomerular and tubulointerstitial injury markers
(fibronectin, connective tissue growth factor, fibroblast-specific protein-1,
collagen I, podocyte vascular endothelial growth factor) in COMT KO mice. We
recently reported that ANG II-mediated tubulointerstitial fibrosis is mediated
by src-dependent epidermal growth factor receptor (EGFR) activation. In aromatic
l-amino acid decarboxylase knockout (AADC KO) mice, a model of intrarenal
dopamine deficiency due to selective proximal tubule AADC deletion, which
inhibits intrarenal dopamine synthesis, ANG II infusion further increased
expression of p-src and pTyr845-EGFR. In contrast, their expression was markedly
attenuated in COMT KO mice. These results demonstrate a role for intrarenal
dopamine to buffer the detrimental effects of ANG II upon the kidney.

Investigators with authorship
Raymond HarrisVanderbilt University