Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats.
We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na(+) clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na(+) accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome-treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated mechanism in the skin to maintain normal blood pressure in states of interstitial Na(+) and Cl(-) accumulation. Failure of this physiological extrarenal regulatory mechanism leads to a salt-sensitive blood pressure response.
Department of Nephrology and Hypertension, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
Agnes
A
Machnik
Anke
A
Dahlmann
Christoph
C
Kopp
Jennifer
J
Goss
Hubertus
H
Wagner
Nico
N
van Rooijen
Kai-Uwe
KU
Eckardt
Dominik N
DN
Müller
Joon-Keun
JK
Park
Friedrich C
FC
Luft
Dontscho
D
Kerjaschki
Jens
J
Titze
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004002:Clodronic Acid / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000166:cytology / Q000502:physiology; D008297:Male; D008901:Mineralocorticoids / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010586:Phagocytes / Q000166:cytology / Q000502:physiology*; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D017673:Sodium Chloride, Dietary / Q000493:pharmacokinetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000502:physiology
D008901:Mineralocorticoids; C492199:Nfat5 protein, rat; D017673:Sodium Chloride, Dietary; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D042582:Vascular Endothelial Growth Factor C; D004002:Clodronic Acid; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D052250:Nitric Oxide Synthase Type III