Chen Y, Harty GJ, Huntley BK, Iyer SR, Heublein DM, Harders GE, Meems L, Pan S, Sangaralingham SJ, Ichiki T, Burnett JC Jr. CRRL269: A novel designer and renal-enhancing pGC-A peptide activator. Am J Physiol Regul Integr Comp Physiol 314: R407–R414, 2018. First published November 29, 2017; doi: 10.1152/ajpregu.00286.2017.—The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions. The mechanism of its cardiorenal selective properties was also inves- tigated. In vitro NP receptor activity was quantified with guanosine 3=,5=-cyclic monophosphate generation. In vivo effects were deter- mined in normal canine acute infusion studies. We observed that CRRL269 demonstrated enhanced pGC-A activity in renal compared with nonrenal cell lines. CRRL269 exerted enhanced resistance to neprilysin compared with URO. Importantly, CRRL269 exhibited significant and greater increases in urinary sodium excretion and diuresis, with less blood pressure reduction, than BNP or URO in normal canines. CRRL269 retained potent renin-angiotensin-aldoste- rone system (RAAS) suppressing properties shared by URO and BNP. Also, CRRL269 exerted less arterial relaxation and higher cAMP cardiomyocytes generation than BNP. CRRL269 possessed superior renal and pGC-A activating properties compared with BNP or URO in vitro. CRRL269 exerted enhanced renal actions while suppressing RAAS in vivo and with less hypotension compared with URO or BNP. Together, our study suggests that CRRL269 is a promising innovative renal-enhancing drug, with favorable protective actions targeting cardiorenal disease states through the pGC-A receptor.