Intrarenal dopamine modulates progressive angiotensin II-mediated renal injury

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.

Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells

“…Systemic chronic infusion of ANG II induces the overexpression of fibronectin and collagen I deposition in the kidney (52). Some of the ANG II-dependent mechanisms involved in the development of CKD involve oxidative stress, intrarenal RAS overactivation, and high blood pressure (11,21,46).…”

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

“…Se ha mostrado que, al envejecer, una exagerada función de los receptores renales AGTR1 está asociada con una disminución en la función del receptor DRD1 y con niveles elevados de presión arterial en modelos de ratón (90). Además, el efecto natriurético de DRD1 es potenciado durante el bloqueo de los receptores AGTR1 (91); y la dopamina, por medio de sus acciones en los receptores DRD1, disminuye la expresión del AGTR1 y los sitios de unión de la angiotensina II en las células del túbulo proximal renal (92,93).…”

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

“…Examples of epithelial stress are ER stress, dysregulation of energy metabolism, G2/M cell cycle arrest (104), autophagy apoptosis, and necrosis (Table 1). Recent studies support the idea that the diseased epithelial cell alone is sufficient to drive fibrosis and CKD (35,105). By using genetic tools to express the human diphtheria toxin receptor only on tubule epithelial cells (35), the investigators showed that repeated selective proximal tubule cell ablation led to interstitial fibrosis, glomerulosclerosis, and capillary rarefaction.…”