First D₁-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring

Abstract

Granda ML, Schroeder FA, Borra RH, Schauer N, Aisaborhale E, Guimaraes AR, Hooker JM. First D 1-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring. Am J Physiol Renal Physiol 307: F116 -F121, 2014. First published May 7, 2014 doi:10.1152/ajprenal.00111.2014.-The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin-angiotensin-aldosterone system. Here, we show the first in vivo measurement of D1-like receptors in the renal cortex of Sprague-Dawley rat and Papio anubis baboon using renal PET; renal dopamine; dopamine; hypertension; positron emission tomography CHRONIC KIDNEY DISEASE exists in 10% of the adult population in the United States and has become a major public health concern and financial burden on the healthcare system (25). The kidneys are largely responsible for controlling important measures of health such as blood pressure and plasma ion concentration, and dysfunction is associated with significant comorbidity including hypertension, diabetes, and cardiovascular disease (5a, 25). Hypertension is the most common chronic medical problem, with a total cost of more than $76 billion to the US economy. Most hypertension is essential (i.e., without a known cause) and a significant number of hypertensive individuals do not respond adequately to current antihypertensive therapies (19).Several distinct dopamine receptor subtypes exist within two families: D 1 -like include D 1 and D 5 receptors, and D 2 -like contain the D 2 , D 3 , and D 4 subtypes. Dopamine signaling is important for the normal functioning of the kidney, and the dysfunction of dopamine receptors has been identified in hypertensive animal models (3,12). It is estimated that 60% of sodium excretion during blood volume expansion is due to the effect of intrarenal dopamine (11). The action of intrarenal dopamine receptors has been leveraged in managing hypertensive crisis and acute kidney damage in humans with exogenous dopamine and the D 1 -like agonist fenoldopam, and can actually improve kidney function in a variety of conditions (13,15,22,24). Recent evidence has shown that specific dopamine receptor subtypes are critical to renal function; in particular, D 1 -like receptor function has been identified as a necessary component for the action of angiotensin II (12). Together, AT1R and D1R are capable of modulating renal sodium excretion. Li et al. (17) reported in 2012 that the interaction between AT1R receptors and D1R is strengthened by the action of angiotensin II blockade, resulting in an increase in D 1 binding potential and concomitant sensitization to dopamine signaling. Biotinylation studies suggest that increased D 1 binding potential is due to an increased B max (i.e., number of D1R at the plasma membrane) via a heightened interaction of D1R with the membrane-bound AT1R. The antihypertensive effect of losa...

The ligand binding ability of dopamine D1 receptors synthesized using a wheat germ cell-free protein synthesis system with liposomes

“…Dopamine released from dendritic cells has been shown to display a novel function in terms of inducing the differentiation of Th17 cells and causing experimental autoimmune encephalitis (Nakano et al, 2008) and antigen-induced neutrophilic airway inflammation (Nakagome et al, 2011). The drugs targeting dopamine D 1 receptors may be useful in the treatment of a wide range of disorders, including Parkinson's disease (Rascol et al, 2001), schizophrenia (Mu et al, 2007), hypertension (Granda et al, 2014), allergy and autoimmune diseases (Nakagome et al, 2011;Nakano et al, 2008 ).…”

Neuroinflammatory component of gray matter pathology in multiple sclerosis

“…In 15 MS subjects (10 SPMS, 5 RRMS) and 11 controls, blood data were sampled from an arterial line during the 90-minutes PET acquisition (2 ml every 6 seconds during the first 3 minutes and at 5-, 10-, 20-, 30-, 60- and 90-minutes post-injection) to generate an arterial plasma input function. Plasma metabolite analysis was performed as previously outlined 28 . In the remaining subjects blood data were not collected either because they preferred not to undergo arterial line placement (N=13) or because an anesthesiologist was not available during PET (N=2).…”

“…Plasma metabolite analysis was performed as previously outlined. 28 In the remaining subjects, blood data were not collected either because subjects preferred not to undergo arterial line placement (n 5 13) or because an anesthesiologist was not available during PET (n 5 2).…”

Antihypertensive mechanisms of intra-renal dopamine

“…[ 11 C]NNC 112, a PET radioligand for D1-like receptors, has previously been used to probe D1-like receptors in the human central nervous system. Granda et al [25] described in-vivo measurement of D1-like receptors in the renal cortex of Sprague-Dawley rat and the Papio anubis baboon by using [ 11 C]NNC 112. They demonstrated that the [ 11 C]NNC 112 binding in the kidney was self-saturable, specific and responsive to drug treatment.…”

“…They demonstrated that the [ 11 C]NNC 112 binding in the kidney was self-saturable, specific and responsive to drug treatment. The use of PET imaging provides a new tool to investigate intrarenal dopamine function in animal models and in humans [25]. …”