cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment.
Defective pressure-natriuresis related to abnormalities in the natriuretic response has been associated with hypertension development. A major signaling pathway mediating pressure natriuresis involves the cGMP-dependent protein kinase 1 (PRKG1) that, once activated by Src kinase, inhibits renal Na(+) reabsorption via a direct action on basolateral Na-K ATPase and luminal Na-H exchanger type 3, as shown in renal tubuli of animals. Because a clear implication of PRKG1 in humans is still lacking, here we addressed whether PRKG1 polymorphisms affect pressure-natriuresis in patients. Naive hypertensive patients (n = 574), genotyped for PRKG1 rs1904694, rs7897633, and rs7905063 single nucleotide polymorphisms (SNPs), underwent an acute Na(+) loading, and the slope of the pressure-natriuresis relationship between blood pressure and Na(+) excretion was calculated. The underlying molecular mechanism was investigated by immunoblotting protein quantifications in human kidneys. The results demonstrate that the PRKG1 risk haplotype GAT (rs1904694, rs7897633, rs7905063, respectively) associates with a rightward shift of the pressure-natriuresis curve (0.017 ± 0.004 μEq/mm Hg per minute) compared with the ACC (0.0013 ± 0.003 μEq/mm Hg per minute; P = 0.001). In human kidneys, a positive correlation of protein expression levels between PRKG1 and Src (r = 0.83; P<0.001) or α1 Na-K ATPase (r = 0.557; P<0.01) and between α1 Na-K ATPase and Na-H exchanger type 3 (r = 0.584; P<0.01) or Src (r = 0.691; P<0.001) was observed in patients carrying PRKG1 risk GAT (n = 23) but not ACC (n = 14) variants. A functional signaling complex among PRKG1, α1 Na-K ATPase, and Src was shown by immunoprecipitation from human renal caveolae. These findings indicate that PRKG1 risk alleles associate with salt-sensitivity related to a loss of the inhibitory control of renal Na(+) reabsorption, suggestive of a blunt pressure-natriuresis response.
San Raffaele Scientific Institute, Nephrology and Dialysis, Università Vita Salute San Raffaele, Via Olgettina 60, 20132 Milan, Italy. manunta.paolo@hsr.it.
Lorena
L
Citterio
Mara
M
Ferrandi
Simona
S
Delli Carpini
Marco
M
Simonini
Tatiana
T
Kuznetsova
Isabella
I
Molinari
Giacomo
G
Dell' Antonio
Chiara
C
Lanzani
Lino
L
Merlino
Elena
E
Brioni
Jan A
JA
Staessen
Giuseppe
G
Bianchi
Paolo
P
Manunta
D000328:Adult; D000368:Aged; D000483:Alleles; D001794:Blood Pressure / Q000235:genetics; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000235:genetics*; D011110:Polymorphism, Genetic; D012964:Sodium / Q000378:metabolism*; D012982:Sodium, Dietary / Q000378:metabolism
D012982:Sodium, Dietary; D012964:Sodium; D062965:Cyclic GMP-Dependent Protein Kinase Type I
PRKG1 protein, human, kidney, natriuresis; pressure-natriuresis; salt-sensitive hypertension; sodium reabsorption