Search

The AGTRAP‐PLOD1 locus is a conserved gene cluster containing several blood pressure regulatory genes, including CLCN6, MTHFR, NPPA, and NPPB. Previous work revealed that knockout of Clcn6 on the Dahl Salt‐Sensitive (SS) rat background (SS‐Clcn6) resulted in lower diastolic blood pressure compared to SS‐WT rats. Additionally, a recent study found sickle cell anemia patients with mutations in CLCN6 had improved survival and reduced stroke risk. We investigated whether loss of Clcn6 would delay the mortality of Dahl SS rats on an 8% NaCl (HS) diet. No significant difference in survival was found. The ability of Clcn6 to affect mRNA expression of nearby Mthfr, Nppa, and Nppb genes was also tested. On normal salt (0.4% NaCl, NS) diets, renal Mthfr mRNA and protein expression were significantly increased in the SS‐Clcn6 rats. MTHFR reduces homocysteine to methionine, but no differences in circulating homocysteine levels were detected. Nppa mRNA levels in cardiac tissue from SS‐Clcn6 rat in both normotensive and hypertensive conditions were significantly reduced compared to SS‐WT. Nppb mRNA expression in SS‐Clcn6 rats on a NS diet was also substantially decreased. Heightened Mthfr expression would be predicted to be protective; however, diminished Nppa and Nppb expression could be deleterious and by preventing or blunting vasodilation, natriuresis, and diuresis that ought to normally occur to offset blood pressure increases. The conserved nature of this genetic locus in humans and rats suggests more studies are warranted to understand how mutations in and around these genes may be influencing the expression of their neighbors. [ABSTRACT FROM AUTHOR]

R4041 --> 724.3 --> Uric acid (UA) homeostasis has been elucidated as a key player in chronic kidney disease and cardiovascular diseases, yet definitive mechanisms are unknown. Previous studies in rodents and humans have shown that increased levels of serum UA predict an activated intrarenal Renin‐Angiotensin‐Aldosterone System (RAAS). In hyperuricemic rats, nephropathy was reported with glomerular hypertrophy and interstitial inflammation accompanied by increased renal renin expression. To explore whether hypouricemia leads to RAAS changes and kidney damage, we utilized a novel rat model with genetic ablation of the Xdh gene in the Dahl salt‐sensitive rat background (SSXdh‐/‐). The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, which produces UA from xanthine and hypoxanthine. We have shown that the SSXdh‐/‐model is hypouricemic and has severe kidney damage. The SSXdh‐/‐ rats demonstrated significant kidney function decline (SSXdh+/+& SSXdh‐/‐respectively, diuresis: 2.7 ± 0.9 & 14.4 ± 5.1 ml; creatinine clearance: 0.51 ± 0.19 & 0.12 ± 0.04 ml/min; and plasma Na+: 136 ± 1.8 & 150 ± 3.7 mmol/l). Quantification of RAAS components was done using liquid chromatography‐tandem mass spectrometry. The comparison of plasma from SSXdh+/+vs SSXdh‐/‐rats revealed significantly lower levels of angiotensin I (650 ± 109, 178 ± 25 pmol/l), Ang II (583 ± 70, 171 ± 16 pmol/l), and renin (indirect measurements using Ang I + Ang II: 1233 ± 172, 349 ± 40 pmol/l). Aldosterone level was increased in SSXdh‐/‐rats (870 ± 115 vs. 4106 ± 1038 pmol/l). The aldosterone/ Ang II ratio was significantly increased in the homozygous rats suggesting enhanced adrenal function (2 ± 0.1, 25 ± 6.3). To further evaluate the contribution of RAAS and its downstream signaling mechanisms, we performed RNA‐Seq analysis on kidney cortex tissue, which showed a number of RAAS‐related genes being differentially expressed between the SSXdh+/+and SSXdh‐/‐ rats. In hypouricemic rats, there was an increase in expression levels of Ace, Ccl2, Fos, Map3k1, Ptger2,and Stat3,and a decrease of Agtr1a, Hsd11b1,and Renb. Therefore, our results show that lack of Xdh/UA leads to kidney injury and functional decline with substantial remodeling in RAAS. [ABSTRACT FROM AUTHOR]

R5255 --> 563.10 --> Our previous studies have suggested that dual treatment of glomerular filtration and albumin reabsorption might be an effective approach to treating salt‐sensitive (SS) hypertension. L‐lysine, an essential amino acid for humans, has been shown to inhibit tubular protein reabsorption with rapidly increasing urinary albumin excretion in healthy male participants. Our recent metabolomics study revealed that intrarenal levels of L‐Lysine are reduced in Dahl SS rats when animals are fed a high salt diet. In our initial experiments, we tested the effects of L‐lysine during the development of hypertension. We found that L‐lysine administration (17 mg/ml drinking water supplement) in SS rats restores albumin balance, triggers diuresis, and diminishes the development of SS hypertension. In our following experiments, we utilized a therapeutic approach to testing the hypothesis that L‐lysine could decrease the blood pressure of subjects with developed hypertension. The SS rats were initially kept on a 0.4% NaCl diet. When they reached 8‐weeks in age, rats were challenged with an 8% NaCl high salt diet (HS) for 10 days until they exceeded an average mean arterial pressure (MAP) of 140 mmHg (N=13; MAP was measured by implanted telemetry). Then, rats were randomly assigned to treatment and control groups. After another 11 days, all rats were euthanized and tissue was collected for further analyses. At the endpoint, the hypertensive L‐lysine treated rats had significantly lower MAP than hypertensive vehicle‐treated rats (145±5 mmHg vs. 176±8 mmHg). Interestingly, therapy with L‐lysine treatment did not result in a significant difference in diuresis or albuminuria. Excretion for all major electrolytes was comparable between the two groups except for Cl‐ (Cl‐/Creatinine for vehicle vs treated: 142±8 & 209±19). Increased excretion in Cl‐ is most likely due to the administration of L‐lysine as a chloride salt. Preliminary analysis using immunohistochemistry suggests less kidney damage in the treatment group compared to the vehicle group. Therefore, our data propose that L‐lysine, when used as a therapeutic, can effectively treat SS hypertension. [ABSTRACT FROM AUTHOR]