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Abstract: PO2519

Kidney Function and Renin-Angiotensin-Aldosterone System in Hypouricemia

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Dissanayake, Lashodya Vindana, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Zietara, Adrian P., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Levchenko, Vladislav, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Palygin, Oleg, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Staruschenko, Alexander, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

Uric acid (UA), the end-product of human purine catabolism, is produced using xanthine dehydrogenase (XDH) and xanthine oxidase enzymes. Both enzymes are encoded by the XDH gene. Disruption of UA homeostasis has been implicated in chronic kidney disease for many years. However, the mechanisms behind the correlation remain unclear. Increased level of UA (hyperuricemia) has been shown to activate the intrarenal Renin-Angiotensin-Aldosterone system (RAAS) in many studies. RAAS in the decreased levels of UA (hypouricemia) has not been studied adequately.

Methods

We have created a new rat model with genetic ablation of the Xdh gene in the Dahl salt-sensitive rat background (SSXdh-/-) to study hypouricemia. RAAS components were quantified using liquid chromatography-tandem mass spectrometry. Rats were kept on a standard diet, and their plasma, urine, and kidneys were collected when they were 6 weeks old. Mean arterial blood pressure (MAP) was measured by using radio telemetry.

Results

The rat model is hypouricemic (UA in plasma 0.25± 0.03 mg/dl & not detectable for SSXdh+/+ & SSXdh-/- respectively). Histology of SSXdh-/- kidneys shows severe damage. The SSXdh-/- rats show renal function decline with different parameters. They demonstrate significantly higher diuresis (2.7± 0.9 & 14.4± 5.1 ml; N=9 & 8 for SSXdh+/+ & SSXdh-/-) , lower creatinine clearance (0.51± 0.19 & 0.12± 0.04 ml/min; N=7 & for both SSXdh+/+ & SSXdh-/-) and Na+ retention (136± 1.8 & 150± 3.7 mmol/l; N=10 & 9 for SSXdh+/+ & SSXdh-/-). The SSXdh-/- rats have significantly lower levels of Angiotensin I/II and Renin and an increased level of Aldosterone compared to SSXdh+/+ rats (Table 1). The 10-week-old SSXdh-/- compared to SSXdh+/+ rats did not have a difference in MAP on the standard diet. When they were challenged with a 4% NaCl diet, they failed to survive.

Conclusion

These results show that the Xdh enzyme is crucial for kidney function, and lack of the enzyme can lead to electrolyte imbalance and changes in RAAS.

Table 1: RAAS in plasma
RAAS componentSSXdh+/+ (pmol/l) (N=5)SSXdh-/- (pmol/l) (N=4)
Angiotensin I (1-10) 650 ± 291178 ± 80*
Angiotensin II (1-8) 583 ± 261 171 ± 77**
Renin (indirect measurement using Ang I + Ang II)1233 ± 551349 ± 156*
Aldosterone870 ± 3894106 ± 1836*

Funding

  • Other NIH Support