Proximal tubule-targeted overexpression of the Cyp4a12-20-HETE synthase promotes salt-sensitive hypertension in male mice

20-Hydroxyeicosatetraenoic acid (20-HETE) has been linked to blood pressure (BP) regulation via actions on the renal microvasculature and tubules. We assessed the tubular 20-HETE contribution to hypertension by generating transgenic mice overexpressing the CYP4A12-20-HETE synthase (PT-4a12 mice) under the control of the proximal tubule (PT)-specific promoter phosphoenolpyruvate carboxykinase (PEPCK). 20-HETE levels in the kidney cortex of male (967 ± 210 vs. 249 ± 69 pg/mg protein) but not female (121 ± 15 vs. 92 ± 11 pg/mg protein) PT-4a12 mice showed a 2.5-fold increase compared with wild type (WT). Renal cortical Cyp4a12 mRNA and CYP4A12 protein in male but not female PT-4a12 mice increased by two- to threefold compared with WT. Male PT-4a12 mice displayed elevated BP (142 ± 1 vs. 111 ± 4 mmHg, P < 0.0001), whereas BP in female PT-4a12 mice was not significantly different from WT (118 ± 2 vs. 117 ± 2 mmHg; P = 0.98). In male PT-4a12 mice, BP decreased when mice were transitioned from a control-salt (0.4%) to a low-salt diet (0.075%) from 135 ± 4 to 120 ± 6 mmHg ( P < 0.01) and increased to 153 ± 5 mmHg ( P < 0.05) when mice were placed on a high-salt diet (4%). Female PT-4a12 mice did not show changes in BP on either low- or high-salt diet. In conclusion, the expression of Cyp4a12 driven by the PEPCK promoter is sex specific, probably because of its X-linkage. The salt-sensitive hypertension seen in PT-4a12 male mice suggests a potential antinatriuretic activity of 20-HETE that needs to be further explored.

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Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20143495 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3495 ◽

Cited By ~ 1

Author(s):

Yanling Yan ◽

Jiayan Wang ◽

Muhammad A. Chaudhry ◽

Ying Nie ◽

Shuyan Sun ◽

...

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Significant Rise ◽

Protein Carbonylation ◽

High Salt ◽

Kidney Cortex ◽

High Salt Diet ◽

Salt Diet ◽

Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

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Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells

AJP Renal Physiology ◽

10.1152/ajprenal.00199.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. F1132-F1141 ◽

Cited By ~ 69

Author(s):

Violeta Alvarez ◽

Yasmir Quiroz ◽

Mayerly Nava ◽

Héctor Pons ◽

Bernardo Rodríguez-Iturbe

Keyword(s):

Interstitial Nephritis ◽

Renal Damage ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Malondialdehyde Content ◽

Induced Hypertension ◽

Salt Sensitive Hypertension ◽

And Control ◽

And Oxidative Stress

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 ± 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg · kg−1 · day−1) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 ± 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

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Abstract 376: The Expression of (pro)renin Receptor is Upregulated in the Kidney by High Salt Diet and No Inhibition

Hypertension ◽

10.1161/hyp.60.suppl_1.a376 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Rong Rong ◽

Osamu Ito ◽

Nobuyoshi Mori ◽

Yuma Tamura ◽

Akihiro Sakuyama ◽

...

Keyword(s):

Collecting Duct ◽

High Salt ◽

Kidney Cortex ◽

Control Group ◽

Thick Ascending Limb ◽

High Salt Diet ◽

Salt Diet ◽

Protein Levels ◽

Nephron Segments ◽

Sd Rats

The (pro)renin receptor ((P)RR)-bound (pro)renin not only causes the generation of angiotensin II via the increased enzymatic activity, it also activates the receptor’s own intracellular signaling pathways up-regulating the expression of the profibrotic proteins. To clarify the regulation of (P)RR expression, the present study examined the effects of high salt diet and nitric oxide synthase (NOS) inhibition on the (P)RR expression in the kidney. The nephron segments were isolated from male Sprague-Dawley (SD) rats by microdissection and bulk isolation technique, and the (P)RR mRNA and protein expressions were examined by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. In adiition, 5 week-old, male SD rats were randomly divided into 3 groups: a control group, a high salt diet (HS) group and a Nω-Nitro-L-arginine (L-NAME) group, and each group was treated with vehicle, high salt diet (8%, NaCl), or L-NAME (600mg/ml in drinking water), respectively. After 4 weeks, the (P)RR expression in the kidney was compared among these groups. The (P)RR mRNA was expressed in the glomerulus (Glm), the proximal convoluted and straight tubule, the cortical and medullary thick ascending limb (TAL) and collecting duct. The (P)RR protein as well as mRNA was expressed widely in the nephron segments; the preglomerular arteriole, the Glm, the proximal tubules (PT), the medullary TAL (mTAL) and inner medullary collecting duct (IMCD). Compared with the control group, the (P)RR protein levels significantly increased in the kidney cortex of both HS group and L-NAME group by 96% (p<0.01) and 506% (p<0.01) and in the inner medulla of L-NAME group by 148% (p<0.05), but did not significantly change in the outer medulla of HS group or L-NAME group. HS increased the (P)RR protein levels in the Glm and PT by 48% (p<0.05) and 39% (p<0.01), but did not affect them in other nephron segments. These results indicated that (P)RR is expressed widely in the nephron segments and that HS and NOS inhibition upregulate the (P)RR expression in the kidney, suggesting roles of (P)RR in hypertensive kidney disorder.

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High-salt diet upregulates activity and mRNA of renal Na(+)-K(+)-ATPase in Dahl salt-sensitive rats

AJP Renal Physiology ◽

10.1152/ajprenal.1993.264.3.f448 ◽

1993 ◽

Vol 264 (3) ◽

pp. F448-F452 ◽

Cited By ~ 2

Author(s):

A. Nishi ◽

G. Celsi ◽

A. Aperia

Keyword(s):

Atpase Activity ◽

Proximal Tubule ◽

Hormonal Regulation ◽

High Salt ◽

Dopa Decarboxylase ◽

Primary Defect ◽

High Salt Diet ◽

Salt Diet ◽

Tubular Cells ◽

Proximal Tubule Segments

We examined the effect of a high-salt (HS) diet on the regulation of renal cortical Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) in young Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The activity of Na(+)-K(+)-ATPase, determined in permeabilized proximal tubule segments, was similar in DS and DR rats on normal salt (NS) diet. HS diet resulted in a twofold increase in proximal tubule Na(+)-K(+)-ATPase activity in DS rats but not in DR rats. The mRNA abundance, which was also similar in DS and DR rats on NS diet, increased after 2 days on HS diet in both innervated and denervated kidneys from DS rats but had no effect in DR rats. The activity of Na(+)-K(+)-ATPase and the content of alpha 1- and beta-protein in cortical homogenate were similar in DS and DR rats on both NS and HS diets. Treatment with benserazide, an inhibitor of dopa decarboxylase, upregulated proximal tubule Na(+)-K(+)-ATPase activity and increased Na(+)-K(+)-ATPase mRNA in DR rats on HS diet. Taken together, these data indicate that there is a primary defect in the dynamic hormonal regulation of Na(+)-K(+)-ATPase activity in intact tubular cells, which might stimulate Na(+)-K(+)-ATPase transcription.

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Renal arteriolar Na+/Ca2+exchange in salt-sensitive hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.4.f567 ◽

1999 ◽

Vol 276 (4) ◽

pp. F567-F573 ◽

Cited By ~ 10

Author(s):

Lawrence D. Nelson ◽

M. Tino Unlap ◽

James L. Lewis ◽

P. Darwin Bell

Keyword(s):

Cytosolic Calcium ◽

Ringer Solution ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Vascular Segment ◽

Low Salt ◽

Afferent Arterioles ◽

Salt Sensitive Hypertension ◽

Exchange Activity

The present studies were performed to assess Na+/Ca2+exchange activity in afferent and efferent arterioles from Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats. Renal arterioles were obtained by microdissection from S and R rats on either a low-salt (0.3% NaCl) or high-salt (8.0% NaCl) diet. On the high-salt diet, S rats become markedly hypertensive. Cytosolic calcium concentration ([Ca2+]i) was measured in fura 2-loaded arterioles bathed in a Ringer solution in which extracellular Na (Nae) was varied from 150 to 2 mM (Na was replaced with N-methyl-d-glucamine). Baseline [Ca2+]iwas similar in afferent arterioles of R and S rats fed low- and high-salt diet. The change in [Ca2+]i(Δ[Ca2+]i) during reduction in Nae from 150 to 2 mM was 80 ± 10 and 61 ± 3 nM (not significant) in afferent arterioles from R rats fed the low- and high-salt diet, respectively. In afferent arterioles from S rats on a high-salt diet, Δ[Ca2+]iduring reductions in Nae from 150 to 2 mM was attenuated (39 ± 4 nM) relative to the Δ[Ca2+]iof 79 ± 13 nM ( P < 0.05) obtained in afferent arterioles from S rats on a low-salt diet. In efferent arterioles, baseline [Ca2+]iwas similar in R and S rats fed low- and high-salt diets, and Δ[Ca2+]iin response to reduction in Naewas also not different in efferent arterioles from R and S rats fed low- or high-salt diets. Differences in regulation of the exchanger in afferent arterioles of S and R rats were assessed by determining the effects of protein kinase C (PKC) activation by phorbol 12-myristate 13-acetate (PMA, 100 nM) on Δ[Ca2+]iin response to reductions in Naefrom 150 to 2 mM. PMA increased Δ[Ca2+]iin afferent arterioles from R rats but not from S rats. These results suggest that Na+/Ca2+exchange activity is suppressed in afferent arterioles of S rats that are on a high-salt diet. In addition, there appears to be a defect in the PKC-Na+/Ca2+exchange pathway that might contribute to altered [Ca2+]iregulation in this important renal vascular segment in salt-sensitive hypertension.

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Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2

AJP Renal Physiology ◽

10.1152/ajprenal.90300.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. F462-F470 ◽

Cited By ~ 103

Author(s):

Peijun P. Shi ◽

Xiao R. Cao ◽

Eileen M. Sweezer ◽

Thomas S. Kinney ◽

Nathan R. Williams ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Critical Role ◽

Specific Inhibitor ◽

Normal Diet ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Ww Domains ◽

Salt Sensitive Hypertension

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

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Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats

AJP Renal Physiology ◽

10.1152/ajprenal.00148.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. F810-F815 ◽

Cited By ~ 18

Author(s):

Laura L. Howard ◽

Matthew E. Patterson ◽

John J. Mullins ◽

Kenneth D. Mitchell

Keyword(s):

Blood Pressure ◽

Renal Plasma Flow ◽

Systolic Pressure ◽

High Salt ◽

Ang Ii ◽

Transgenic Rats ◽

High Salt Diet ◽

Blood Pressure Elevation ◽

Salt Diet ◽

Salt Sensitive Hypertension

Transient exposure to ANG II results in the development of salt-sensitive hypertension in rats. This study was performed to determine whether a transient hypertensive episode can induce salt-sensitive hypertension in transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name TGR(Cyp1a1-Ren2)]. Systolic blood pressures were measured in conscious male Cyp1a1-Ren2 rats ( n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days. Systolic pressure increased from 135 ± 5 to 233 ± 7 mmHg by day 14. I3C administration was terminated and blood pressure returned to normal levels (137 ± 5 mmHg) within 10 days. Subsequently, the rats were placed on a high-salt diet (8% NaCl) for 10 days. Systolic pressure increased by 34 ± 2 mmHg throughout 10 days of the high-salt diet. Neither glomerular filtration rate nor renal plasma flow was altered in Cyp1a1-Ren2 rats with salt-sensitive hypertension. In a separate group of male Cyp1a1-Ren2 rats ( n = 6) transiently induced with 0.15% I3C for 14 days, administration of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, 2 mM) attenuated the increase in systolic pressure induced by high salt. Systolic pressure increased by only 11 ± 1 mmHg throughout 8 days of a high-salt diet and tempol administration. Thus transient induction of ANG II-dependent hypertension via activation of the Cyp1a1-Ren2 transgene induces salt-sensitive hypertension in these transgenic rats. The attenuation by tempol of the high salt-induced blood pressure elevation indicates that ANG II-induced production of superoxide anion contributes to the development of salt-sensitive hypertension after transient induction of ANG II-dependent hypertension.

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Post-cyclosporine-mediated hypertension and nephropathy: amelioration by vascular endothelial growth factor

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.4.f727 ◽

2001 ◽

Vol 280 (4) ◽

pp. F727-F736 ◽

Cited By ~ 79

Author(s):

Duk-Hee Kang ◽

Yoon-Goo Kim ◽

Takeshi F. Andoh ◽

Katherine L. Gordon ◽

Shin-Ichi Suga ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

High Salt ◽

Vascular Endothelial ◽

Tubulointerstitial Injury ◽

Angiogenic Growth Factors ◽

High Salt Diet ◽

Salt Diet ◽

Salt Sensitive Hypertension ◽

Endothelial Growth Factor

Recent studies have demonstrated a role for microvascular and tubulointerstitial injury in some models of salt-sensitive hypertension. We utilized a model of post-cyclosporin A (CsA) nephropathy and hypertension to test the hypothesis that treatment with an angiogenic factor aimed at ameliorating the microvascular and renal injury would prevent the development of hypertension. CsA was administered with a low-salt diet for 45 days, resulting in a renal lesion characterized by afferent arteriolopathy, focal peritubular capillary loss, and tubulointerstitial fibrosis. Rats were then placed on a high-salt diet and randomized to receive either vascular endothelial growth factor (VEGF121) or vehicle for 14 days. Placement of rats with established CsA nephropathy on a high-salt diet results in the rapid development of salt-sensitive hypertension. VEGF121 treatment resulted in lower blood pressure, and this persisted on discontinuing the VEGF. VEGF121 treatment was also associated with a decrease in osteopontin expression, macrophage infiltration, and collagen III deposition and markedly stimulated resolution of the arteriolopathy (20.9 ± 7.8 vs. 36.9 ± 6.1%, VEGF vs. vehicle, P < 0.05). In conclusion, CsA-associated renal microvascular and tubulointerstitial injury results in the development of salt-sensitive hypertension. Treatment of animals with established CsA nephropathy with VEGF reduces the hypertensive response and accelerates histological recovery. The vascular protective effect of VEGF may be due to the improvement of arteriolopathy. Angiogenic growth factors may represent a novel strategy for treating CsA-associated hypertension and renal disease.

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Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.2.f303 ◽

1999 ◽

Vol 277 (2) ◽

pp. F303-F311 ◽

Cited By ~ 41

Author(s):

John D. Imig ◽

Gabriel L. Navar ◽

Li-Xian Zou ◽

Katie C. O’Reilly ◽

Patricia L. Allen ◽

...

Keyword(s):

High Salt ◽

Dietary Sodium ◽

Kidney Cortex ◽

Ang Ii ◽

Converting Enzyme ◽

High Salt Diet ◽

Salt Diet ◽

Angiotensin Peptides ◽

Low Salt ◽

Ace Activity

Kidney cortex and proximal tubular angiotensin II (ANG II) levels are greater than can be explained on the basis of circulating ANG II, suggesting intrarenal compartmentalization of these peptides. One possible site of intracellular accumulation is the endosomes. In the present study, we tested for endosomal ANG I, ANG II, angiotensin type 1A receptor (AT1A), and angiotensin converting enzyme (ACE) activity and determined whether these levels are regulated by salt intake. Male Sprague-Dawley rats were fed chow containing either high or low dietary sodium for 10–14 days. Blood and kidneys were harvested and processed for measurement of plasma, kidney, and renal intermicrovillar cleft and endosomal angiotensin levels. Kidney ANG I averaged 179 ± 20 fmol/g and ANG II averaged 258 ± 36 fmol/g in rats fed a high-sodium diet and were significantly higher, averaging 347 ± 58 fmol/g and 386 ± 55 fmol/g, respectively, in rats fed a low-salt diet. Renal intermicrovillar clefts and endosomes contained ANG I and ANG II. Intermicrovillar cleft ANG I and ANG II levels averaged 8.4 ± 2.6 and 74 ± 26 fmol/mg, respectively, in rats fed a high-salt diet and 7.6 ± 1.7 and 70 ± 25 fmol/mg in rats fed a low-salt diet. Endosomal ANG I and ANG II levels averaged 12.3 ± 4.4 and 43 ± 19 fmol/mg, respectively, in rats fed a high-salt diet, and these levels were similar to those observed in rats fed a low-salt diet. Renal endosomes from rats fed a low-salt diet demonstrated significantly more AT1A receptor binding compared with rats fed a high-salt diet. ACE activity was detectable in renal intermicrovillar clefts and was 2.5-fold higher than the levels observed in renal endosomes. Acute enalaprilat treatment decreased ACE activity in renal intermicrovillar clefts by 90% and in renal endosomes by 84%. Likewise, intermicrovillar cleft and endosomal ANG II levels decreased by 61% and 52%, respectively, in enalaprilat-treated animals. These data demonstrate the presence of intact angiotensin peptides and ACE activity in renal intermicrovillar clefts and endosomes, indicating that intact angiotensin peptides are formed and/or trafficked through intracellular endosomal compartments and are dependent on ACE activity.

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Abstract 666: Monoclonal Anti-marinobufagenin Antibody Alters Profile Of Expression Of Profibrotic Genes In Aorta In Hypertensive Dahl-S Rats

Hypertension ◽

10.1161/hyp.60.suppl_1.a666 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Olga V Fedorova ◽

Victoria Shilova ◽

Courtney A Marshall ◽

Yongqing Zhang ◽

Elin Lehrmann ◽

...

Keyword(s):

Vascular Remodeling ◽

Cardiac Fibrosis ◽

High Salt ◽

Tgfβ Signaling ◽

High Salt Diet ◽

Salt Diet ◽

Uremic Cardiomyopathy ◽

Low Salt ◽

Salt Sensitive Hypertension ◽

Paired Analysis

Elevated levels of cardiotonic steroid marinobufagenin (MBG) are implicated in pathogenesis of salt-sensitive hypertension in Dahl-S rats (DS), and induce cardiac fibrosis in rats with experimental uremic cardiomyopathy. We hypothesized that in hypertensive DS immunoneutralization of MBG with a monoclonal antibody (Mab) would affect expression of profibrotic genes and would exhibit anti-remodeling effects. We studied following groups (n=6 each): (1) DS on a low salt (0.3% NaCl) diet (LS); (2) DS on a high salt (8% NaCl) diet for 7 weeks (HS); (3) DS on a high salt diet for 7 weeks, following 3E9 anti-MBG Mab treatment for 5 days (HSAB). Levels of MBG, and levels of mRNA expression in aorta (microarray analysis, Illumina) were assessed. In HS vs. LS, BP increased by 78 mmHg (p<0.01), plasma MBG doubled (p<0.05), renal MBG excretion increased 6-fold (p<0.01), and relative weights of aortae increased (4.44±0.17 vs. 3.01±0.06 mg/mm x kg BW, p<0.01). In HSAB, BP decreased by 35 mmHg (p<0.01), and weights of aortae were markedly reduced (3.72±0.06 mg/mm x kg BW; p<0.01) vs. HS. In hypertensive DS, genes implicated in TGFβ-signaling (Table) were up-regulated, and were down-regulated following immunoneutralization of MBG. Thus, MBG participates in vascular remodeling in DS, and immunoneutralization of MBG produces an anti-remodeling effect associated with down-regulation of genes implicated in TGFβ-induced pro-fibrotic signaling. Table . Z-ratio of paired analysis of gene expression in aorta:

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