Intrarenal dopamine modulates progressive angiotensin II-mediated renal injury.

Yang S, Yao B, Zhou Y, Yin H, Zhang MZ, Harris RC
Am J Physiol Renal Physiol. 2012 302 (6): F742-9

PMID: 22169008 · PMCID: PMC3311314 · DOI:10.1152/ajprenal.00583.2011

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.

MeSH Terms (15)

Angiotensin II Animals Aromatic-L-Amino-Acid Decarboxylases Blood Pressure Catechol O-Methyltransferase Cells, Cultured Dopamine Gene Expression Regulation, Enzymologic Kidney Kidney Tubules, Proximal Mice Mice, Knockout Renin-Angiotensin System RNA, Messenger src-Family Kinases

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