Genetic Knockout of Cingulin‐like 1 Reduces Renal Injury and Blood Pressure in Dahl Salt‐Sensitive Rats

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.

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Chronic Nicotine Worsens Blood Pressure and Renal Injury on Hyperandrogenemic Female Rats

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.593.7 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Rodrigo Oscar Maranon ◽

Jane F. Reckelhoff

Keyword(s):

Blood Pressure ◽

Renal Injury ◽

Female Rats ◽

Chronic Nicotine

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Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression

Physiological Genomics ◽

10.1152/physiolgenomics.00089.2002 ◽

2003 ◽

Vol 12 (3) ◽

pp. 229-237 ◽

Cited By ~ 50

Author(s):

Mingyu Liang ◽

Baozhi Yuan ◽

Elizabeth Rute ◽

Andrew S. Greene ◽

Michael Olivier ◽

...

Keyword(s):

Blood Pressure ◽

Renal Injury ◽

Time Course ◽

Expression Patterns ◽

Renal Medulla ◽

Temporal Patterns ◽

Reference Distribution ◽

Arterial Blood ◽

Renal Tubular ◽

Salt Sensitive Hypertension

Dahl salt-sensitive SS and consomic, salt-resistant SS-13BN/Mcw rats possess a highly similar genetic background but exhibit substantial differences in blood pressure salt sensitivity. We used cDNA microarrays to examine sequential changes of mRNA expression of ∼2,000 currently known rat genes in the renal medulla (a tissue critical for long-term blood pressure regulation) in SS and SS-13BN/Mcw rats in response to a high-salt diet (16 h, 3 days, or 2 wk). Differentially expressed genes in each between-group comparison were identified based on a threshold determined experimentally using a reference distribution that was constructed by comparing rats within the same group. A difference analysis of 54 microarrays identified 50 genes that exhibited the most distinct temporal patterns of expression between SS and SS-13BN/Mcw rats over the entire time course. Thirty of these genes could be linked to the regulation of arterial blood pressure or renal injury based on their known involvement in functional pathways such as renal tubular transport, metabolism of vasoactive substances, extracellular matrix formation, and apoptosis. Importantly, the majority of the 30 genes exhibited temporal expression patterns that would be expected to lower arterial pressure and reduce renal injury in SS-13BN/Mcw compared with SS rats. The phenotypic impact of the other 20 genes was less clear. These 50 genes are widely distributed on chromosome 13 and several other chromosomes. This suggested that primary genetic defects, although important, are unlikely to be solely responsible for the full manifestation of this type of hypertension and associated injury phenotypes. In summary, the results of this study identified a number of pathways potentially important for the amelioration of hypertension and renal injury in SS-13BN/Mcw rats, and these results generated a series of testable hypotheses related to the role of the renal medulla in the complex mechanism of salt-sensitive hypertension.

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Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II-induced hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00281.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. F161-F169 ◽

Cited By ~ 35

Author(s):

Miguel L. Graciano ◽

Akira Nishiyama ◽

Keith Jackson ◽

Dale M. Seth ◽

Rudy M. Ortiz ◽

...

Keyword(s):

Blood Pressure ◽

Cell Proliferation ◽

Renal Injury ◽

Mesangial Cell ◽

Cell Transformation ◽

Receptor Activation ◽

Macrophage Infiltration ◽

Receptor Blocker ◽

Ang Ii ◽

Actin Expression

Chronic ANG II infusions lead to increases in intrarenal ANG II levels, hypertension, and tissue injury. Increased blood pressure also elicits increases in renal interstitial fluid (RIF) ATP concentrations that stimulate cell proliferation. We evaluated the contribution of purinergic receptor activation to ANG II-induced renal injury in rats by treating with clopidogrel, a P2Y12 receptor blocker, or with PPADS, a nonselective P2 receptor blocker. α-Actin expression in mesangial cells, afferent arteriolar wall thickness (AAWT), cortical cell proliferation, and macrophage infiltration were used as early markers of renal injury. Clopidogrel and PPADS did not alter blood pressure, renin or kidney ANG II content. α-Actin expression increased from control of 0.6 ± 0.4% of mesangial area to 6.3 ± 1.9% in ANG II-infused rats and this response was prevented by clopidogrel (0.4 ± 0.2%) and PPADS. The increase in AAWT from 4.7 ± 0.1 to 6.0 ± 0.1 mm in ANG II rats was also prevented by clopidogrel (4.8 ± 0.1 mm) and PPADS. ANG II infusion led to interstitial macrophage infiltration (105 ± 16 vs. 62 ± 4 cell/mm2) and tubular proliferation (71 ± 15 vs. 20 ± 4 cell/mm2) and these effects were prevented by clopidogrel (52 ± 4 and 36 ± 3 cell/mm2) and PPADS. RIF ATP levels were higher in ANG II-infused rats than in control rats (11.8 ± 1.9 vs. 5.6 ± 0.6 nmol/l, P < 0.05). The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation, renal inflammation, and vascular hypertrophy observed in ANG II-dependent hypertension.

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Abstract P111: ELABELA Antagonizes Intrarenal Renin to Lower Blood Pressure and Protect Against Renal Injury

Hypertension ◽

10.1161/hyp.72.suppl_1.p111 ◽

2018 ◽

Vol 72 (Suppl_1) ◽

Author(s):

Chuanming Xu ◽

Fei Wang ◽

Yanting Chen ◽

Shiying Xie ◽

Renfei Luo ◽

...

Keyword(s):

Blood Pressure ◽

Renal Injury ◽

Lower Blood Pressure ◽

Lower Blood

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

International Journal of Molecular Sciences ◽

10.3390/ijms21062248 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2248 ◽

Cited By ~ 1

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.

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OS 21-09 DIPPING PATTERN OF BLOOD PRESSURE AND RENAL INJURY IN DAHL SALT-SENSITIVE HYPERTENSIVE RATS

Journal of Hypertension ◽

10.1097/01.hjh.0000500528.66210.82 ◽

2016 ◽

Vol 34 (Supplement 1) ◽

pp. e237

Author(s):

Akira Nishiyama ◽

Abu Sufiun ◽

Yoshihide Fujisawa ◽

Asadur Rahman ◽

Daisuke Nakano ◽

...

Keyword(s):

Blood Pressure ◽

Renal Injury ◽

Hypertensive Rats

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Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00187.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. R803-R812 ◽

Cited By ~ 30

Author(s):

Jussara M. do Carmo ◽

Lakshmi S. Tallam ◽

John V. Roberts ◽

Elizabeth L. Brandon ◽

John Biglane ◽

...

Keyword(s):

Blood Pressure ◽

Renal Injury ◽

Salt Sensitivity ◽

Metabolic Abnormalities ◽

Salt Diet ◽

Melanocortin 4 Receptor ◽

Renal Structure ◽

Long Term Impact ◽

And Function

The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R−/−) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R−/− and WT mice made hypertensive by NG-nitro-l-arginine methyl ester (l-NAME) in the drinking water for 8 wk. Old MC4R−/− mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 ± 2 and 117 ± 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [ΔMAP: MC4R (−/−) 4 ± 2 mmHg; WT, 2 ± 1 mmHg]. Obese MC4R−/− mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-β and collagen expression were not significantly different between old MC4R−/− and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R−/− than WT mice. Mild increases in MAP during l-NAME treatment (∼16 mmHg) caused small, but greater, elevations in UAE, renal TGF-β content, and macrophage infiltration in MC4R−/− compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R−/− mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R−/− mice are protected from renal injury by mechanisms that are still unclear.

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