A fluorogenic near-infrared imaging agent for quantifying plasma and local tissue renin activity in vivo and ex vivo.
The renin-angiotensin system (RAS) is well studied for its regulation of blood pressure and fluid homeostasis, as well as for increased activity associated with a variety of diseases and conditions, including cardiovascular disease, diabetes, and kidney disease. The enzyme renin cleaves angiotensinogen to form angiotensin I (ANG I), which is further cleaved by angiotensin-converting enzyme to produce ANG II. Although ANG II is the main effector molecule of the RAS, renin is the rate-limiting enzyme, thus playing a pivotal role in regulating RAS activity in hypertension and organ injury processes. Our objective was to develop a near-infrared fluorescent (NIRF) renin-imaging agent for noninvasive in vivo detection of renin activity as a measure of tissue RAS and in vitro plasma renin activity. We synthesized a renin-activatable agent, ReninSense 680 FAST (ReninSense), using a NIRF-quenched substrate derived from angiotensinogen that is cleaved specifically by purified mouse and rat renin enzymes to generate a fluorescent signal. This agent was assessed in vitro, in vivo, and ex vivo to detect and quantify increases in plasma and kidney renin activity in sodium-sensitive inbred C57BL/6 mice maintained on a low dietary sodium and diuretic regimen. Noninvasive in vivo fluorescence molecular tomographic imaging of the ReninSense signal in the kidney detected increased renin activity in the kidneys of hyperreninemic C57BL/6 mice. The agent also effectively detected renin activity in ex vivo kidneys, kidney tissue sections, and plasma samples. This approach could provide a new tool for assessing disorders linked to altered tissue and plasma renin activity and to monitor the efficacy of therapeutic treatments.
PerkinElmer, Boston, Massachusetts, USA.
Jun
J
Zhang
Dorin V
DV
Preda
Kristine O
KO
Vasquez
Jeff
J
Morin
Jeannine
J
Delaney
Bagna
B
Bao
M David
MD
Percival
Daigen
D
Xu
Dan
D
McKay
Michael
M
Klimas
Bohumil
B
Bednar
Cyrille
C
Sur
David Z
DZ
Gao
Karen
K
Madden
Wael
W
Yared
Milind
M
Rajopadhye
Jeffrey D
JD
Peterson
D000821:Animal Feed / Q000032:analysis; D000818:Animals; D002402:Cathepsin D; D056649:Cathepsin G; D005260:Female; D005456:Fluorescent Dyes / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D012083:Renin / Q000097:blood* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D012680:Sensitivity and Specificity; D012982:Sodium, Dietary
D005456:Fluorescent Dyes; D010455:Peptides; D012982:Sodium, Dietary; D007703:Peptidyl-Dipeptidase A; D056649:Cathepsin G; D012083:Renin; D002402:Cathepsin D