Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

Abstract

In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc -/-mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc -/-mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E 2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild-type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity.

Regulation of glomerulotubular balance. I. Impact of dopamine on flow-dependent transport

“…Proximal tubules are also a target for the locally generated dopamine, with inhibition of apical Na/H-exchange (NHE3) and basolateral Na-K-ATPase (3). A mouse model in which the intrarenal dopamine is deficient becomes hypertensive with increased NHE3, Na ϩ -K ϩ -2Cl Ϫ cotransporter 2 (NKCC2), Na ϩ -HCO 3 Ϫ contransporter (NBC), Na ϩ -Cl Ϫ cotransporter (NCC), and aquaporin 2 (AQP2) mRNA expression in the kidney (45), consistent with dopamine downregulation of Na ϩ transport in the kidney. In opossum kidney (OK) cells, the dopamine-induced acute decrease in surface NHE3 is dependent on both DA1 and DA2 receptors, and dopamine-stimulated NHE3 endocytosis can be blocked by protein kinase A (PKA) inhibition or by mutation of PKA target serines on NHE3 (22).…”

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

“…Los efectos de la dopamina mediados por los receptores D1 (DRD1) se han asociado con la regulación de la presión arterial por medio de la estimulación de la diuresis y natriuresis, y del aumento de la vasodilatación (85,86). La activación de DRD1 por la dopamina responde por el 50 % de la excreción de sodio en condiciones basales (87); por ello, la deficiencia intrarrenal de dopamina puede llevar a hipertensión (88). Además, la secuencia que codifica el miR-504 se encuentra en el cromosoma X; por lo tanto, la modulación de la expresión de estos receptores por parte de este microARN puede jugar un papel importante en la influencia del sexo sobre el riesgo de hipertensión.…”

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

“…Norepinephrine affects the sympathetic nervous system and parts of the brain involving attention and arousal [43,44]. Dopamine has broad effects, including immune, endocrine, kidney, gastrointestinal, and pancreatic functions, as well as the regulation of body weight and life span length [45,46,47,48]. TCAs could also degrade the functioning of many adaptive processes.…”