Dietary Influences on the Dahl SS Rat Gut Microbiota and its effects on Salt‐Sensitive Hypertension and Renal Damage

High blood pressure affects 1.39 billion adults across the globe and is the leading preventable cause of death worldwide. Hypertension is a multifaceted disease with known genetic and environmental factors contributing to its progression. Our studies utilizing the Dahl salt-sensitive (SS) rat have demonstrated the remarkable influence of dietary protein and maternal environment on the development of hypertension and renal damage in response to high salt. There is growing interest in the relationship between the microbiome and hypertension, with gut dysbiosis being correlated to a number of pathologies. This review summarizes the current literature regarding the interplay among dietary protein, the gut microbiota, and hypertension. These studies may provide insight into the effects we have observed between diet and hypertension in Dahl SS rats and, we hope, lead to new perspectives where potential dietary interventions or microbiota manipulations could serve as plausible therapies for hypertension.

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Abstract P174: Sex Differences In The Pro-hypertensive Effect Of Carnitine, The Precursor Of Gut-derived Metabolite TMAO

Hypertension ◽

10.1161/hyp.78.suppl_1.p174 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Justine M Abais-Battad ◽

John Henry Dasinger ◽

David L Mattson

Keyword(s):

Gut Microbiota ◽

Antibiotic Treatment ◽

Renal Damage ◽

Elevated Pressure ◽

High Salt ◽

Male Rats ◽

Oral Antibiotic ◽

Gut Inflammation ◽

Reduced Salt ◽

Salt Sensitive Hypertension

Recent evidence reports sexually divergent mechanisms that differentially drive the severity of hypertension. Our data show that female Dahl Salt-Sensitive (SS) rats are significantly protected from salt-induced hypertension and renal injury and have stark differences in gut microbiota composition compared to males. Gut-derived metabolites are increasingly being recognized as mechanistic links between the gut microbiota and hypertension. One such metabolite is trimethylamine N-oxide (TMAO), which is derived from the bacterial metabolism of carnitine and is gaining notoriety for its role in cardiovascular disease. Metabolomics analysis in high salt-fed SS rats revealed a trend for increased TMAO (1.3-fold, p=0.11) in the serum of males compared to females (n=6). TMAO appears to be specifically derived from gut bacteria since oral antibiotic treatment nearly eliminated circulating TMAO levels in both males and females (99.3% and 88.9% reduction, respectively; p<0.001). Interestingly, antibiotic treatment reduced salt-sensitive hypertension in males but not females. There was also a corresponding increase in the TMAO precursor carnitine (1.9-fold, p<0.01) in the serum of males versus females. Thus, we hypothesized that administration of carnitine (400 mg/kg/day) in the drinking water would exacerbate salt-sensitive hypertension, renal damage, and gut inflammation in male and female SS rats challenged with high salt (4% NaCl). There was a trend for carnitine treatment to exacerbate mean arterial pressure in both males (160±9 vs 146±2 mmHg, n=4-6, p=0.22) and females (155±6 vs 139±2 mmHg, n=2, p=0.14) compared to vehicle. Despite elevated pressure in both sexes, carnitine-treated males exhibited greater increases in albuminuria (340±136 vs 194±29 mg/day, carnitine vs vehicle, p=0.28) than females (55±33 vs 26±5 mg/day). Carnitine treatment also significantly increased the number of CD3+ T cells in the colonic lamina propria (24.3±6.0 vs 2.4±0.5 x 10 6 cells/g tissue, n=5, p<0.05) of male rats compared to vehicle. Together, these data identify gut microbiota-mediated carnitine/TMAO metabolism as a potentially detrimental pathway that promotes greater salt-sensitivity, renal damage, and gut inflammation in males versus females.

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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 P332: Role of T-Lymphocytes in the Long-Term Blood Pressure and Renal Disease Effects of Acute Renal Ischemia-Reperfusion Injury

Hypertension ◽

10.1161/hyp.68.suppl_1.p332 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Bernardo Lopez ◽

Galina Petrova ◽

Justine M Abais-Battad ◽

Hayley Lund ◽

Daniel Fehrenbach ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Renal Damage ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Immunosuppressive Agents ◽

High Salt ◽

Renal Ischemia ◽

Salt Sensitive Hypertension

Epidemiological data indicates that acute kidney injury (AKI) is an independent risk factor for the development of hypertension and chronic kidney disease in patients. Previous studies demonstrated that rats develop sodium-dependent hypertension and kidney damage following experimental AKI induced by a renal ischemia-reperfusion (IR) insult; furthermore, these high salt deleterious effects could be blunted by administration of immunosuppressive agents. The present study was performed on Dahl SS (SS) rats and SS rats with a null mutation in the CD247 gene (SS-CD247) leading to depletion of T-lymphocytes in order to specifically examine the role of T cells in this response (n=5-6 rats/group). As assessed by serum creatinine (SCr) levels, no difference was observed in the initial response to IR injury between SS and SS-CD247: SCr increased from 0.44±0.03 to 2.16±0.32 mg/dl in SS rats 24 hours after an initial 30 minute period of renal ischemia and returned to control levels after 8 days of recovery. Moreover, no differences were noted in mean arterial pressure (MAP) or albumin excretion rate (UAlb) between SS and SS-CD247 after 43 days of recovery from IR injury while the rats were maintained on a low salt (0.4% NaCl) diet. When the rats were fed a 4.0% NaCl diet for two weeks, MAP and UAlb significantly increased in the sham SS to 178±9 mmHg and 189±25 mg/day, respectively; values significantly greater than observed in the sham SS-CD247 rats (148±2 mmHg and 87±17 mg/day). As expected, the SS rats recovered from IR injury demonstrated an exaggerated increase in MAP (peaking at 183±2 mmHg) and UAlb (275±54 mg/day) in response to high salt. There was no difference in the number of total CD3+ lymphocytes in the kidneys of IR and sham SS after high salt, though the ratio of CD4+/CD8+ T cells was increased in the IR group. Compared to sham CD247, an exaggerated elevation of MAP (157±9 mmHg) and UAlb (210±32 mg/day) was also observed in the SS-CD247 rats recovered from IR injury, demonstrating enhanced responsiveness following IR injury in animals lacking T cells. These data indicate that T lymphocytes amplify salt-sensitive hypertension and renal damage, but other mechanisms also mediate the salt-sensitive hypertension and renal damage that occurs in animals recovered from IR injury.

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Integrated Fecal Microbiome and Serum Metabolomics Analysis Reveals Abnormal Changes in Rats with Immunoglobulin A Nephropathy and the Intervention Effect of Zhen Wu Tang

Frontiers in Pharmacology ◽

10.3389/fphar.2020.606689 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jicheng Li ◽

Yiwen Cao ◽

Ruirui Lu ◽

Honglian Li ◽

Yu Pang ◽

...

Keyword(s):

Gut Microbiota ◽

Renal Disease ◽

Intestinal Microbiota ◽

Renal Damage ◽

Immunoglobulin A ◽

Metabolic Phenotype ◽

Immunoglobulin A Nephropathy ◽

Metabolic Phenotypes ◽

Potential Relationship ◽

Rdna Sequencing

Immunoglobulin A nephropathy (IgAN), an autoimmune renal disease with complicated pathogenesis, is one of the principal reasons for end-stage renal disease in the clinic. Evidence has linked apparent alterations in the components of the microbiome and metabolome to renal disease in rats. However, thus far, there is insufficient evidence that supports the potential relationship between gut microbiome, circulating metabolites, and IgAN. This study was designed to probe the effects of IgAN on intestinal microecology and metabolic phenotypes and to understand the possible underlying mechanisms. Fecal and serum samples were collected from IgAN rats. Composition of the gut microbiota and biochemical changes in the metabolites was analyzed using 16S rDNA sequencing and untargeted metabolomics. The IgAN rats exhibited renal insufficiency and increased concentration of 24-h urine protein, in addition to deposition of IgA and IgG immune complexes in the kidney tissues. There was a disturbance in the balance of gut microbiota in IgAN rats, which was remarkably associated with renal damage. Marked changes in microbial structure and function were accompanied by apparent alterations in 1,403 serum metabolites, associated with the disorder of energy, carbohydrate, and nucleotide metabolisms. Administration of Zhen Wu Tang ameliorated microbial dysbiosis and attenuated the renal damage. Besides, treatment with Zhen Wu Tang modulated the metabolic phenotype perturbation in case of gut microbiota dysbiosis in IgAN rats. In conclusion, these findings provided a comprehensive understanding of the potential relationship between the intestinal microbiota and metabolic phenotypes in rats with IgAN. Elucidation of the intestinal microbiota composition and metabolic signature alterations could identify predictive biomarkers for disease diagnosis and progression, which might contribute to providing therapeutic strategies for IgAN.

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Impact of lincosamides antibiotics on the composition of the rat gut microbiota and the metabolite profile of plasma and feces

Toxicology Letters ◽

10.1016/j.toxlet.2018.08.002 ◽

2018 ◽

Vol 296 ◽

pp. 139-151 ◽

Cited By ~ 3

Author(s):

C. Behr ◽

S. Ramírez-Hincapié ◽

H.J. Cameron ◽

V. Strauss ◽

T. Walk ◽

...

Keyword(s):

Gut Microbiota ◽

Metabolite Profile ◽

Rat Gut

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Dietary Effects on Dahl Salt-Sensitive Hypertension, Renal Damage, and the T Lymphocyte Transcriptome

Hypertension ◽

10.1161/hypertensionaha.119.12927 ◽

2019 ◽

Vol 74 (4) ◽

pp. 854-863 ◽

Cited By ~ 10

Author(s):

Justine M. Abais-Battad ◽

Ammar J. Alsheikh ◽

Xiaoqing Pan ◽

Daniel J. Fehrenbach ◽

John Henry Dasinger ◽

...

Keyword(s):

T Lymphocyte ◽

Renal Damage ◽

Dietary Effects ◽

Salt Sensitive Hypertension

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Inflammatory macrophages in the kidney contribute to salt-sensitive hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00454.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. F544-F548 ◽

Cited By ~ 2

Author(s):

Daniel J. Fehrenbach ◽

David L. Mattson

Keyword(s):

Renal Damage ◽

Macrophage Polarization ◽

Adverse Side Effects ◽

Pyrin Domain ◽

Inflammatory Phenotype ◽

Inflammatory Macrophages ◽

Salt Sensitive Hypertension ◽

The Relationship ◽

Hyperosmotic Environment ◽

Receptor Family

This review will highlight recent studies that have investigated the relationship between Na+, renal macrophage polarization, and renal damage. A hyperosmotic environment drives the macrophage toward a proinflammatory phenotype and away from an anti-inflammatory phenotype. Animal models of salt-sensitive hypertension demonstrate a characteristic infiltration of macrophages into the kidney that is greatly reduced when blood pressure is lowered. Because general immunosuppression or macrophage depletion leads to a host of adverse side effects, more recent studies have modulated the interaction of specific signaling molecules, including NOD-like receptor family pyrin domain-containing 3, chemokine (C-X-C motif) ligand 16, and VEGF, to prevent the end-organ renal damage that accumulates in salt-sensitive disease.

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