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Lack of Xdh Leads to Alterations in Renin‐Angiotensin‐Aldosterone System and Kidney Injury
Author(s) -
Dissanayake Lashodya V.,
Zietara Adrian,
Levchenko Vladislav,
Palygin Oleg,
Staruschenko Alexander
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r4041
Subject(s) - medicine , endocrinology , aldosterone , renin–angiotensin system , chemistry , kidney , renal function , uric acid , angiotensin ii , receptor , blood pressure
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 (SS Xdh‐/‐ ). The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, which produces UA from xanthine and hypoxanthine. We have shown that the SS Xdh‐/‐ model is hypouricemic and has severe kidney damage. The SS Xdh‐/‐ rats demonstrated significant kidney function decline (SS Xdh+/+ & SS Xdh‐/‐ 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 SS Xdh+/+ vs SS Xdh‐/‐ 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 SS Xdh‐/‐ 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 SS Xdh+/+ and SS Xdh‐/‐ 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.