CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension

Studies examining mechanisms of Dahl salt-sensitive (SS) hypertension have implicated the infiltration of leukocytes in the kidneys, which contribute to renal disease and elevated blood pressure. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. The present study nominated a signaling pathway by analyzing a kidney RNA sequencing data set from SS rats fed either a low-salt (0.4% NaCl) diet or a high-salt (4.0% NaCl) diet. From this analysis, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) receptor 2 (CCR2) were nominated as a potential pathway modifying renal leukocyte infiltration and contributing to SS hypertension. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS-102895 at 5 mg·kg−1·day−1 in DMSO) or DMSO vehicle for 3 or 21 days by intraperitoneal injections during the high salt challenge. Blood pressure, renal leukocyte infiltration, and renal damage were evaluated. The results demonstrated that RS-102895 treatment ameliorated renal damage (urinary albumin excretion; 43.4 ± 5.1 vs. 114.7 ± 15.2 mg/day in vehicle, P < 0.001) and hypertension (144.3 ± 2.2 vs. 158.9 ± 4.8 mmHg in vehicle, P < 0.001) after 21 days of high-salt diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the high-salt diet (1.4 ± 0.1 vs. 1.9 ± 0.2 in vehicle × 106 CD45+ cells/kidney, P = 0.034). An in vitro chemotaxis assay validated the effect of RS-102895 on leukocyte chemotaxis toward CCL2. The results suggest that increased CCL2 in SS kidneys is important in the early recruitment of leukocytes, and blockade of this recruitment by administering RS-102895 subsequently blunted the renal damage and hypertension.

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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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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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Alamandine alleviates hypertension and renal damage via oxidative-stress attenuation in Dahl rats

Cell Death Discovery ◽

10.1038/s41420-022-00822-y ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Juexiao Gong ◽

Man Luo ◽

Yonghong Yong ◽

Shan Zhong ◽

Peng Li

Keyword(s):

Oxidative Stress ◽

Renal Dysfunction ◽

Renal Damage ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Renal Tubular Cells ◽

Induced Hypertension

AbstractAlamandine (Ala) is a novel member of the renin–angiotensin-system (RAS) family. The present study aimed to explore the effects of Ala on hypertension and renal damage of Dahl salt-sensitive (SS) rats high-salt diet-induced, and the mechanisms of Ala on renal-damage alleviation. Dahl rats were fed with high-salt diets to induce hypertension and renal damage in vivo, and HK-2 cells were treated with sodium chloride (NaCl) to induce renal injury in vitro. Ala administration alleviated the high-salt diet-induced hypertension, renal dysfunction, and renal fibrosis and apoptosis in Dahl SS rats. The HK-2 cells’ damage, and the increases in the levels of cleaved (c)-caspase3, c-caspase8, and c-poly(ADP-ribose) polymerase (PARP) induced by NaCl were inhibited by Ala. Ala attenuated the NaCl-induced oxidative stress in the kidney and HK-2 cells. DETC, an inhibitor of SOD, reversed the inhibitory effect of Ala on the apoptosis of HK-2 cells induced by NaCl. The NaCl-induced increase in the PKC level was suppressed by Ala in HK-2 cells. Notably, PKC overexpression reversed the moderating effects of Ala on the NaCl-induced apoptosis of HK-2 cells. These results show that Ala alleviates high-salt diet-induced hypertension and renal dysfunction. Ala attenuates the renal damage via inhibiting the PKC/reactive oxygen species (ROS) signaling pathway, thereby suppressing the apoptosis in renal tubular cells.

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Multiple blood pressure loci on rat chromosome 13 attenuate development of hypertension in the Dahl S hypertensive rat

Physiological Genomics ◽

10.1152/physiolgenomics.00280.2006 ◽

2007 ◽

Vol 31 (2) ◽

pp. 228-235 ◽

Cited By ~ 59

Author(s):

Carol Moreno ◽

Mary L. Kaldunski ◽

Tao Wang ◽

Richard J. Roman ◽

Andrew S. Greene ◽

...

Keyword(s):

Blood Pressure ◽

Renal Damage ◽

High Salt ◽

Male Rats ◽

Brown Norway ◽

High Salt Diet ◽

Salt Diet ◽

Chromosome 13 ◽

Congenic Strains ◽

Multiple Blood

Previous studies have indicated that substitution of chromosome 13 of the salt-resistant Brown Norway BN/SsNHsdMcwi (BN) rat into the genomic background of the Dahl salt-sensitive SS/JrHsdMcwi (SS) rat attenuates the development of salt-sensitive hypertension and renal damage. To identify the regions within chromosome 13 that attenuate the development of hypertension during a high-salt diet in the SS rat, we phenotyped a series of overlapping congenic lines covering chromosome 13, generated from an intercross between the consomic SS-13BN rat and the SS rat. Blood pressure was determined in chronically catheterized rats after 2 wk of high-salt diet (8% NaCl) together with microalbuminuria as an index of renal damage. Four discrete regions were identified, ranging in size from 4.5 to 16 Mbp, each of which independently provided significant protection from hypertension during high-salt diet, reducing blood pressure by 20–29 mmHg. Protection was more robust in female than male rats in some of the congenic strains, suggesting a sex interaction with some of the genes determining blood pressure during high-salt diet. Among the 23 congenic strains, several regions overlapped. When three of the “protective” regions were combined onto one broad congenic strain, no summation effect was seen, obtaining the same decrease in blood pressure as with each one independently. We conclude from these studies that there are four regions within chromosome 13 containing genes that interact epistatically and influence arterial pressure.

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Dietary Salt Modifies the Blood Pressure Response to Renin-Angiotensin Inhibition in Experimental Chronic Kidney Disease

AJP Renal Physiology ◽

10.1152/ajprenal.00603.2020 ◽

2021 ◽

Author(s):

Dominique M Bovee ◽

Estrellita Uijl ◽

David Severs ◽

Eloisa Rubio-Beltrán ◽

Richard van Veghel ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

High Salt ◽

Dietary Salt ◽

High Salt Diet ◽

Salt Diet ◽

Renin Angiotensin ◽

Water Accumulation ◽

Salt Sensitive Hypertension

Chronic kidney disease (CKD) contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared to sham, 5/6Nx rats had lower NHE3, NKCC2, NCC, a-ENaC and Kir4.1, but higher SKG1, prostasin, g-ENaC, and Kir5.1. These differences correlated with plasma renin, aldosterone, and/or potassium. On a normal salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 mmHg and -43 ± 9 mmHg). A high salt diet caused skin sodium and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat CKD model, salt-sensitive hypertension develops with a selective increase in g-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, while a high salt diet causes more severe hypertension mediated through the mineralocorticoid receptor.

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Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00221.2006 ◽

2006 ◽

Vol 291 (6) ◽

pp. F1281-F1287 ◽

Cited By ~ 29

Author(s):

Martha Franco ◽

Flavio Martínez ◽

Bernardo Rodríguez-Iturbe ◽

Richard J. Johnson ◽

José Santamaría ◽

...

Keyword(s):

Blood Pressure ◽

Inflammatory Cells ◽

Acute Effect ◽

High Salt ◽

Acute Administration ◽

Ang Ii ◽

High Salt Diet ◽

Salt Diet ◽

Interstitial Inflammation ◽

Salt Sensitive Hypertension

Transient administration of ANG II causes persistent salt-sensitive hypertension associated with arteriolopathy, interstitial inflammation, and cortical vasoconstriction; blocking the vascular and inflammatory changes with mycophenolate mofetil (MMF) prevents vasoconstriction. While infiltrating leukocytes during the salt-sensitive hypertension phase express ANG II, the functional role of ANG II during this phase is not known. We examined the acute effect of candesartan on renal hemodynamics during the established salt-sensitive hypertensive phase and related these findings to direct measurement of intrarenal ANG II and inflammatory cells in rats previously exposed to ANG II with or without MMF treatment. Sham controls were also examined. The administration of ANG II, followed by exposure to high-salt diet, resulted in hypertension, cortical vasoconstriction, an increase in interstitial inflammatory cells (44.8 ± 1.3 lymphocytes/mm2, and 30.8 ± 1.2 macrophages/mm2 ANG II vs. 19.6 ± 2 lymphocytes/mm2, and 22 ± 0.7 macrophages/mm2 Sham), and increase in renal ANG II levels (1,358 ± 74.6 pg/ml ANG II vs. 194 ± 9.28 pg/ml Sham). Treatment with MMF during the administration of exogenous ANG II resulted in reduction in renal interstitial inflammation (19.7 ± 0.9 lymphocytes/mm2 and 15.9 ± 0.8 machophages/mm2), ANG II levels (436.9 ± 52.29 pg/ml), cortical vasoconstriction, and stable blood pressure levels during the subsequent challenge with a high-salt diet. Acute administration of candesartan similarly reduced renal vasoconstriction and blood pressure. We conclude that the cortical vasoconstriction occurring with salt-sensitive hypertension following exposure to ANG II is mediated by intrarenal ANG II, related, at least in part, to the interstitial inflammation.

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AT1 receptor regulation in salt-sensitive hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.5.h1701 ◽

1999 ◽

Vol 277 (5) ◽

pp. H1701-H1707 ◽

Cited By ~ 11

Author(s):

Kerstin Strehlow ◽

Georg Nickenig ◽

Jörg Roeling ◽

Sven Wassmann ◽

Oliver Zolk ◽

...

Keyword(s):

Blood Pressure ◽

High Salt ◽

Receptor Regulation ◽

Ang Ii ◽

Receptor Density ◽

Pressure Regulation ◽

High Salt Diet ◽

Salt Diet ◽

Receptor Mrna ◽

Salt Sensitive Hypertension

The molecular events governing salt-sensitive hypertension are currently unknown. Because the renin-ANG system plays a central role in blood pressure regulation and electrolyte balance, it may be closely involved in the phenomenon of salt sensitivity. Therefore, we examined the effect of a high-salt diet (8%) and a low-salt diet (0.4%) on ANG II-caused vascular constriction and ANG II type 1 (AT1) receptor expression in aorta, brain, and kidney of Dahl S (salt-sensitive) and Dahl R (salt-resistant) rats by means of radioligand binding assays and quantitative PCR. NaCl diet at 8% led to a significant increase of blood pressure in Dahl S but not in Dahl R rats. High-sodium intake caused a profound decrease of ANG II-induced aortic vasoconstriction in both Dahl R and Dahl S rats. The underlying mechanism was a downregulation of aortic AT1receptor density and AT1 receptor mRNA. AT1 receptor mRNA was downregulated to 57.8% in Dahl R and 59.0% in Dahl S rats by an 8% NaCl diet compared with a 0.4% NaCl diet ( P < 0.05). There was a similar decrease in aortic AT1 receptor density. Additionally, AT1receptor mRNA was also downregulated in the kidney but upregulated the brain of Dahl R and S rats on a high-salt diet. Thus high NaCl intake causes organ-specific AT1 receptor regulation in Dahl R and in Dahl S rats despite the differential blood pressure regulation in these animal models in response to a high-salt diet. These findings suggest that the regulation of vascular AT1 receptors is influenced by numerous factors such as the renin-ANG system and obviously by various other events that are currently only partly understood.

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Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition

AJP Renal Physiology ◽

10.1152/ajprenal.2001.281.1.f38 ◽

2001 ◽

Vol 281 (1) ◽

pp. F38-F47 ◽

Cited By ~ 123

Author(s):

Yasmir Quiroz ◽

Héctor Pons ◽

Katherine L. Gordon ◽

Jaimar Rincón ◽

Maribel Chávez ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Mycophenolate Mofetil ◽

Washout Period ◽

Renal Injury ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Renal Histology ◽

Salt Sensitive Hypertension

Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N ω-nitro-l-arginine-methyl ester (l-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg · kg−1 · day−1 by gastric gavage), followed by a 1-wk “washout” period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially.l-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.

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