scholarly journals PGI2 Analog Attenuates Salt-Induced Renal Injury through the Inhibition of Inflammation and Rac1-MR Activation

2020 ◽  
Vol 21 (12) ◽  
pp. 4433
Author(s):  
Daigoro Hirohama ◽  
Wakako Kawarazaki ◽  
Mitsuhiro Nishimoto ◽  
Nobuhiro Ayuzawa ◽  
Takeshi Marumo ◽  
...  
Keyword(s):  
Renal Injury ◽  
Renal Damage ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Renal Inflammation ◽  
Beraprost Sodium ◽  
Anti Inflammatory ◽  
Stage Renal Disease ◽  
End Stage

Renal inflammation is known to be involved in salt-induced renal damage, leading to end-stage renal disease. This study aims to evaluate the role of inflammation in anti-inflammatory and renoprotective effects of beraprost sodium (BPS), a prostaglandin I2 (PGI2) analog, in Dahl salt-sensitive (DS) rats. Five-week-old male DS rats were fed a normal-salt diet (0.5% NaCl), a high-salt diet (8% NaCl), or a high-salt diet plus BPS treatment for 3 weeks. BPS treatment could inhibit marked proteinuria and renal injury in salt-loaded DS rats with elevated blood pressure, accompanied by renal inflammation suppression. Notably, high salt increased renal expression of active Rac1, followed by increased Sgk1 expressions, a downstream molecule of mineralocorticoid receptor (MR) signal, indicating salt-induced activation of Rac1-MR pathway. However, BPS administration inhibited salt-induced Rac1-MR activation as well as renal inflammation and damage, suggesting that Rac1-MR pathway is involved in anti-inflammatory and renoprotective effects of PGI2. Based upon Rac1 activated by inflammation, moreover, BPS inhibited salt-induced activation of Rac1-MR pathway by renal inflammation suppression, resulting in the attenuation of renal damage in salt-loaded DS rats. Thus, BPS is efficacious for the treatment of salt-induced renal injury.

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.

Abstract 16835: Targeted Disruption of Paraoxonase 3 in a Dahl Salt-Sensitive Rat Model of Chronic Kidney Disease Increases Renal Cortical Pro-Inflammatory Eicosanoids

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Chrysan J Mohammed ◽  
Fatimah K Khalaf ◽  
Prabhatchandra Dube ◽  
Tyler J Reid ◽  
Jacob A Connolly ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Renal Cortex ◽  
High Salt ◽  
High Density Lipoproteins ◽  
Wild Type ◽  
Targeted Disruption ◽  
High Salt Diet ◽  
Salt Diet ◽  
Mediators Of Inflammation

Background: Paraoxonase 3 (Pon3), is one of the three isoforms of the paraoxonase gene family. While Pon1 and Pon2 are widely studied, there is a paucity of knowledge regarding Pon3. Pon3 is synthesized in the liver and can circulate bound to high-density lipoproteins. There is significant expression in the kidney also. Pon3 has the ability to metabolize eicosanoids, which can act as signaling molecules and have known roles in the pathophysiology of some renal diseases. Decreased Pon activity is associated with elevated levels of eicosanoid metabolites and adverse clinical outcomes. We tested the hypothesis that targeted disruption of Pon3 results in elevated levels of pro-inflammatory eicosanoids and progression of renal injury. Methods/ Results: Ten week old male Dahl salt-sensitive (SS rats) and Pon3 mutant rats (SS Pon3 KO) were maintained on 8% high salt diet for eight weeks, to initiate salt-sensitive hypertensive renal disease. Previously we observed that SS Pon3 KO rats on eight weeks high salt diet demonstrated significantly increased phenotypic renal injury and mortality. In the current study, we noted that SS Pon3 KO had significantly decreased (p<0.05) glomerular filtration rate compared to SS wild type. Blood pressure (radiotelemetry) as well as plasma angiotensin and aldosterone (LC-MS/MS) were not different between the two groups after high salt diet. We used targeted lipidomic profiling to determine eicosanoid content in renal cortex from SS Pon3 KO and SS wild type rats at the end of eight weeks of high salt diet. We found that hydroxyl fatty acids 5-HEPE and 5-HETE (5-lipoxygenase dependent arachidonic acid metabolites) were significantly (p<0.05) elevated in the renal cortex of SS Pon3 KO compared to SS wild type rats. In addition to being mediators of inflammation, these metabolites are associated with renal cell injury and death. Furthermore, prostaglandin 6-keto-PGF 1α , which has known links to renal inflammation, was significantly (p<0.05) increased in renal cortex of SS- Pon3 KO compared to SS wild type rats. Conclusion: These findings suggest that targeted deletion of Pon3 increases pro-inflammatory eicosanoids (5-HETE and 5-HEPE) and prostaglandins (6-keto-PGF 1α ), as well as increases renal damage independent of blood pressure.

scholarly journals Association of a Disrupted Dipping Pattern of Blood Pressure with Progression of Renal Injury during the Development of Salt-Dependent Hypertension in Rats

2020 ◽  
Vol 21 (6) ◽  
pp. 2248 ◽  
Author(s):  
Abu Sufiun ◽  
Asadur Rahman ◽  
Kazi Rafiq ◽  
Yoshihide Fujisawa ◽  
Daisuke Nakano ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Rhythm ◽  
Renal Injury ◽  
Tissue Injury ◽  
Renal Tissue ◽  
High Salt ◽  
Hypertensive Rats ◽  
High Salt Diet ◽  
Salt Diet ◽  
The Difference

The aim of the present study is to investigate whether a disruption of the dipping pattern of blood pressure (BP) is associated with the progression of renal injury in Dahl salt-sensitive (DSS) hypertensive rats. Seven-week-old DSS rats were fed a high salt diet (HSD; 8% NaCl) for 10 weeks, followed by a transition to a normal salt diet (NSD; 0.3% NaCl) for 4 weeks. At baseline, NSD-fed DSS rats showed a dipper-type circadian rhythm of BP. By contrast, HSD for 5 days caused a significant increase in the difference between the active and inactive periods of BP with an extreme dipper type of BP, while proteinuria and renal tissue injury were not observed. Interestingly, HSD feeding for 10 weeks developed hypertension with a non-dipper pattern of BP, which was associated with obvious proteinuria and renal tissue injury. Four weeks after switching to an NSD, BP and proteinuria were significantly decreased, and the BP circadian rhythm returned to the normal dipper pattern. These data suggest that the non-dipper pattern of BP is associated with the progression of renal injury during the development of salt-dependent hypertension.

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

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.

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

2007 ◽  
Vol 31 (2) ◽  
pp. 228-235 ◽  
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.

The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet

2010 ◽  
Vol 25 (6) ◽  
pp. 549-555 ◽  
Author(s):  
Shizuka Aritomi ◽  
Hajime Koganei ◽  
Hirotaka Wagatsuma ◽  
Akira Mitsui ◽  
Tetsuya Ogawa ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Renal Injury ◽  
Channel Blocker ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet

scholarly journals Sodium bicarbonate loading limits tubular cast formation independent of glomerular injury and proteinuria in Dahl salt-sensitive rats

2018 ◽  
Vol 132 (11) ◽  
pp. 1179-1197 ◽  
Author(s):  
Sarah C. Ray ◽  
Bansari Patel ◽  
Debra L. Irsik ◽  
Jingping Sun ◽  
Hiram Ocasio ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Bicarbonate ◽  
Renal Injury ◽  
High Salt ◽  
Proton Channel ◽  
Pathological Feature ◽  
Glomerular Injury ◽  
High Salt Diet ◽  
Salt Diet ◽  
Inflammatory Status

Sodium bicarbonate (NaHCO3) slows the decline in kidney function in patients with chronic kidney disease (CKD), yet the mechanisms mediating this effect remain unclear. The Dahl salt-sensitive (SS) rat develops hypertension and progressive renal injury when fed a high salt diet; however, the effect of alkali loading on kidney injury has never been investigated in this model. We hypothesized that NaHCO3 protects from the development of renal injury in Dahl salt-sensitive rats via luminal alkalization which limits the formation of tubular casts, which are a prominent pathological feature in this model. To examine this hypothesis, we determined blood pressure and renal injury responses in Dahl SS rats drinking vehicle (0.1 M NaCl) or NaHCO3 (0.1 M) solutions as well as in Dahl SS rats lacking the voltage-gated proton channel (Hv1). We found that oral NaHCO3 reduced tubular NH4+ production, tubular cast formation, and interstitial fibrosis in rats fed a high salt diet for 2 weeks. This effect was independent of changes in blood pressure, glomerular injury, or proteinuria and did not associate with changes in renal inflammatory status. We found that null mutation of Hv1 also limited cast formation in Dahl SS rats independent of proteinuria or glomerular injury. As Hv1 is localized to the luminal membrane of TAL, our data suggest that alkalization of the luminal fluid within this segment limits cast formation in this model. Reduced cast formation, secondary to luminal alkalization within TAL segments may mediate some of the protective effects of alkali loading observed in CKD patients.

Abstract 500: The Cardiorenal Effects Of An Angiotensin Receptor Blocker (Valsartan) And Neprilysin Inhibitor (AHU377) Co-administered Daily For 6 Weeks In The Dahl Salt-sensitive Rat Model Of Volume-dependent Hypertension

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Alexander J McNamara ◽  
Laxminarayan G Hegde ◽  
Uwe Klein ◽  
Craig Hill ◽  
Cecile Yu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Weight Gain ◽  
Rat Model ◽  
Renal Injury ◽  
Body Weight Gain ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Neprilysin Inhibitor

The endogenous natriuretic peptide system helps maintain cardiovascular homeostasis by counterbalancing the deleterious effects of renin angiotensin system activation. This study examined whether the co-administration of an ARB (valsartan: VAL) with a NEPi (AHU377: AHU) can reduce cardiorenal disease progression in the Dahl salt-sensitive (Dahl/SS) rat model of volume-dependent hypertension. Methods: Studies were conducted in conscious Dahl/SS hypertensive rats that were maintained on a high salt diet and surgically implanted with telemetry transmitters for monitoring blood pressure. Rats were treated for 6 weeks with either vehicle, VAL (30 mg/kg, PO) or VAL+AHU (30 + 30 mg/kg, PO). Changes in cardiac and renal functions were measured via Left Ventricle (LV) pressure-volume loops and biomarkers (KIM-1, NGAL and osteopontin). Results: Dahl/SS rats maintained on a high salt diet exhibited a progressive decrease in body weight gain, progressive increases in blood pressure and elevation of plasma and urinary biomarkers indicative of cardiac stress or renal injury. VAL and VAL+AHU both improved body weight gain and blunted the progressive hypertension. However, the magnitude of the antihypertensive effect was greater for VAL+AHU (peak change: - 33 ± 3 mmHg) than for VAL alone (peak change: -15 ± 5 mmHg). VAL+AHU treatment provided greater renal protective effects, based on renal biomarkers KIM-1 (286 ± 29 vs. 341 ± 59 ng), NGAL (58 ±9 vs. 108 ± 28 μg) and osteopontin (1637 ± 372 vs 2155 ± 748 ng), than VAL alone. The VAL+AHU treatment group demonstrated a greater normalization in LV function, with improved systolic contractility over VAL alone (preload-adjusted PWR max = 1 ± 0.1 vs. 2 ± 0.5 μWatt/uL). Most notably, the VAL+AHU group exhibited a greater survival rate (94%: 15 of 16) than either the VAL (75%: 12 of 16) or vehicle (70%: 14 of 20) groups. Conclusion: In summary, chronic co-administration of an ARB and NEPi to Dahl/SS rats significantly attenuated progression of hypertension, suppressed increases in biomarkers indicative of renal injury, improved cardiac function and increased overall survival. These results suggest that co-administration of an ARB and NEPi may confer a beneficial therapeutic strategy for the treatment of cardiorenal disease.

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