Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long-term antihypertensive effects.
NO deficiency is associated with development of hypertension. Defects in the renal citrulline-arginine pathway or arginine reabsorption potentially reduce renal NO in prehypertensive spontaneously hypertensive rats (SHRs). Hence, we investigated genes related to the citrulline-arginine pathway or arginine reabsorption, amino acid pools, and renal NO in 2-week-old prehypertensive SHRs. In addition, because perinatally supporting NO availability reduces blood pressure in SHRs, we supplemented SHR dams during pregnancy and lactation with citrulline, the rate-limiting amino acid for arginine synthesis. In female offspring, gene expression of argininosuccinate synthase (involved in renal arginine synthesis) and renal cationic amino acid Y-transporter (involved in arginine reabsorption) were both decreased in 2-day and 2-week SHRs compared with normotensive WKY, although no abnormalities in amino acid pools were observed. In addition, 2-week-old female SHRs had much less NO in their kidneys (0.46+/-0.01 versus 0.68+/-0.05 nmol/g of kidney weight, respectively; P<0.001) but not in their heart. Furthermore, perinatal supplementation with citrulline increased renal NO to 0.59+/-0.02 nmol/g of kidney weight (P<0.001) at 2 weeks and persistently ameliorated the development of hypertension in females and until 20 weeks in male SHR offspring. Defects in both the renal citrulline-arginine pathway and in arginine reabsorption precede hypertension in SHRs. We propose that the reduced cationic amino acid transporter disables the developing SHR kidney to use arginine reabsorption to compensate for reduced arginine synthesis, resulting in organ-specific NO deficiency. This early renal deficiency and its adverse sequels can be corrected by perinatal citrulline supplementation persistently in female and transiently in male SHRs.
Koeners
Maarten P
MP
Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands.
van Faassen
Ernst E
EE
Wesseling
Sebastiaan
S
de Sain-van der Velden
Monique
M
Koomans
Hein A
HA
Braam
Branko
B
Joles
Jaap A
JA
D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D002956:Citrulline / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis* / Q000172:deficiency; D019001:Nitric Oxide Synthase / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D011918:Rats, Inbred SHR
D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D000959:Antihypertensive Agents; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D001124:Argininosuccinate Synthase