Salt-Sensitive Hypertension of the Renal Tubular Cell–Specific NFAT5 (Nuclear Factor of Activated T-Cells 5) Knockout Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Akiko Hiramatsu ◽  
Yuichiro Izumi ◽  
Koji Eguchi ◽  
Naomi Matsuo ◽  
Qinyuan Deng ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Urinary Sodium Excretion ◽  
High Salt ◽  
Sodium Reabsorption ◽  
Renal Tubular Cell ◽  
Activated T Cells ◽  
High Salt Diet ◽  
Renal Tubular ◽  
Salt Sensitive Hypertension

The kidney plays a crucial role in blood pressure (BP) regulation by controlling sodium reabsorption along the nephron. NFAT5 (nuclear factor of activated T-cells 5) is a transcription factor that is expressed in various tissues including the kidney and is activated at hypertonic conditions as observed in the renal medulla; the role for kidney NFAT5 in BP regulation, however, remains still obscure. In the present study, we generated inducible and renal tubular cell–specific NFAT5 knockout (KO) mice and characterized their phenotype. The NFAT5 KO mice exhibited high BP, hypernatremia, polyuria, and low urinary sodium excretion without significant alterations in the plasma renin activity or aldosterone concentration. The mice fed a high-salt diet further increased BP, revealing salt-sensitive hypertension. The KO mice ehibited the increased gene expression of the epithelial sodium channel. Protein expression of epithelial sodium channel in the membrane fraction was also significantly increased in KO mice than in wild-type mice. Treatment with amiloride, an epithelial sodium channel blocker, corrected high BP, hypernatremia, and decreased urinary sodium excretion in KO mice to the same levels of those in wild-type mice. Finally, the effects of high-salt diet and amiloride in KO mice were confirmed by the radiotelemetry method. In conclusion, these data indicate that renal tubular NFAT5 should play an important role in regulating sodium reabsorption through epithelial sodium channel under high-salt conditions, thereby preventing salt-dependent hypertension.

scholarly journals Epithelial Sodium Channel and Salt-Sensitive Hypertension

Hypertension ◽  
2021 ◽  
Vol 77 (3) ◽  
pp. 759-767
Author(s):  
Stephanie M. Mutchler ◽  
Annet Kirabo ◽  
Thomas R. Kleyman
Keyword(s):  
Blood Pressure ◽  
Sodium Channel ◽  
Salt Intake ◽  
Extracellular Fluid ◽  
Pressure Rise ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

Linkage of Nedd4, a Regulator of the Epithelial Sodium Channel, to Primary Hypertension in Blacks

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 685-685
Author(s):  
J. Howard Pratt ◽  
John F Rebhun ◽  
Leah L Flury ◽  
Tatiana Foroud
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
Chromosome 15 ◽  
Allele Sharing ◽  
Sibling Pairs ◽  
Affected Sibling ◽  
Show Evidence ◽  
Py Motif ◽  
Salt Sensitive Hypertension

40 Salt-sensitive hypertension is common in blacks. A primary renal mechanism may account for the increase in sodium reabsorption since levels of mineralocorticoids, including aldosterone, are often reduced in blacks. Albeit milder, the hypertension in blacks resembles Liddle s syndrome, where mutations in the epithelial sodium channel result in increased numbers of functioning channels and sodium retention. In Liddle s syndrome, molecular mutations in the PY-motif at the COOH-terminus of either the α- or β-subunit prevents binding of Nedd4, an ubiquitin ligase that targets channels for removal from the cell surface. Thus, Nedd4 is a candidate mediator of risk for hypertension in blacks. To evaluate Nedd4 s role, we performed linkage analyses in 86-88 black hypertensive sib pairs. Subjects were genotyped for two highly polymorphic markers, D15S126 and D15S1016, with heterozygosity of 79% and 89%, respectively. Both are within a 5 cM interval of chromosome 15 that contains KIAA0093 or Nedd4. Among the affected sibling pairs, we observed increased allele sharing for D15S126 (π = 0.57; p=0.01) and D15S1016 (π =0.55; p=0.07). Using only hypertensive sibling pairs (n=42-45 pairs) with BMI <32 kg/M 2 resulted in greater allele sharing for both D15S126 (π =0.63; p=0.0001) and D15S1016 (π =0.57; p=0.06). In summary, we show evidence for linkage of hypertension to a region on chromosome 15 containing the gene for Nedd4. While these results need to be confirmed in other samples, they suggest that variability in Nedd4 or a nearby gene(s) confers a strong influence on differences in sodium homeostasis and blood pressure in blacks.

scholarly journals Involvement of Vanin-1 in Ameliorating Effect of Oxidative Renal Tubular Injury in Dahl-Salt Sensitive Rats

2019 ◽  
Vol 20 (18) ◽  
pp. 4481 ◽  
Author(s):  
Keiko Hosohata ◽  
Denan Jin ◽  
Shinji Takai ◽  
Kazunori Iwanaga
Keyword(s):  
Treatment Effect ◽  
High Salt ◽  
Tubular Damage ◽  
Tubular Injury ◽  
Renal Tubular Damage ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Renal Tubular ◽  
Salt Sensitive Hypertension

In salt-sensitive hypertension, reactive oxygen species (ROS) play a major role in the progression of renal disease partly through the activation of the mineralocorticoid receptor (MR). We have previously demonstrated that urinary vanin-1 is an early biomarker of oxidative renal tubular injury. However, it remains unknown whether urinary vanin-1 might reflect the treatment effect. The objective of this study was to clarify the treatment effect for renal tubular damage in Dahl salt-sensitive (DS) rats. DS rats (six weeks old) were given one of the following for four weeks: high-salt diet (8% NaCl), high-salt diet plus a superoxide dismutase mimetic, tempol (3 mmol/L in drinking water), high-salt diet plus eplerenone (100 mg/kg/day), and normal-salt diet (0.3% NaCl). After four-week treatment, blood pressure was measured and kidney tissues were evaluated. ROS were assessed by measurements of malondialdehyde and by immunostaining for 4-hydroxy-2-nonenal. A high-salt intake for four weeks caused ROS and histological renal tubular damages in DS rats, both of which were suppressed by tempol and eplerenone. Proteinuria and urinary N-acetyl-β-D-glucosaminidase exhibited a significant decrease in DS rats receiving a high-salt diet plus eplerenone, but not tempol. In contrast, urinary vanin-1 significantly decreased in DS rats receiving a high-salt diet plus eplerenone as well as tempol. Consistent with these findings, immunohistochemical analysis revealed that vanin-1 was localized in the renal proximal tubules but not the glomeruli in DS rats receiving a high-salt diet, with the strength attenuated by tempol or eplerenone treatment. In conclusion, these results suggest that urinary vanin-1 is a potentially sensitive biomarker for ameliorating renal tubular damage in salt-sensitive hypertension.

Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC

2021 ◽  
pp. ASN.2020081112
Author(s):  
Luciana C. Veiras ◽  
Justin Z. Y. Shen ◽  
Ellen A. Bernstein ◽  
Giovanna C. Regis ◽  
DuoYao Cao ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Reabsorption ◽  
High Salt Diet ◽  
Salt Diet ◽  
Diabetic Kidney ◽  
Salt Sensitive Hypertension

BackgroundHypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown.MethodsFemale and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension.ResultsMale, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti–IL-6 antibody, prevented the development of salt sensitivity in male db/db mice.ConclusionsThe inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.

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

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
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.

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

2002 ◽  
Vol 283 (5) ◽  
pp. F1132-F1141 ◽  
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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