Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway.
OBJECTIVE
This study assessed whether the Rho kinase signaling pathway contributes to androgenic amplification of angiotensin II (Ang II) induced pressor and renal constrictor responses.


METHODS
Mean arterial pressure (MAP) responses to angiotensin II receptor 1 (AT1) inhibition were measured in conscious male New Zealand genetically hypertensive rats (NZGH) subjected to sham operation, castration or castration+testosterone replacement. MAP and renal vascular resistance (RVR) responses to Ang II were recorded with and without a Rho kinase inhibitor, fasudil, in anesthetized NZGH. Western blot was used to analyze target protein expression in the kidney.


RESULTS
MAP responses to AT1 receptor inhibition and exogenous Ang II were attenuated in castrated NZGH. The increase in RVR (mm Hg/ml/min/g kidney) at the maximum dose of Ang II was significantly lower in castrated NZGH than in sham operated NZGH. Testosterone replacement restored RVR responses to Ang II in castrated rats. Fasudil treatment reduced both MAP and RVR responses to Ang II in each group. In addition, the differential MAP and RVR responses to Ang II amongst the three groups were significantly attenuated by Rho kinase inhibition. Western blot showed that Rho kinase protein expression was reduced by castration, while testosterone replacement restored the Rho kinase protein levels in castrated rats. The phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a downstream target of Rho kinase, was also increased by androgens.


CONCLUSIONS
Collectively, these results indicate that androgens potentiate Ang II-induced renal vascular responses, an effect mediated at least partly via up-regulation of the Rho kinase signaling pathway.
Song
Jin
J
Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Kost
Curtis K
CK
Martin
Douglas S
DS
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D004789:Enzyme Activation; D006977:Hypertension, Renal / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009919:Orchiectomy; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000378:metabolism; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D012082:Renal Veins / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D054460:rho-Associated Kinases
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000804:Angiotensin II; D013739:Testosterone; D004656:Enalapril; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; C049347:fasudil