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Abstract: SA-OR077

Inhibition of Urea Transporter A Attenuates Uremic Cardiomyopathy in CKD Mouse

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Kuma, Akihiro, Emory University Renal Division, Atlanta, United States
  • Wang, Xiaonan H., Emory University Renal Division, Atlanta, Georgia, United States
  • Klein, Janet D., Emory University Renal Division, Atlanta, Georgia, United States
  • Sands, Jeff M., Emory University Renal Division, Atlanta, Georgia, United States
Background

Chronic kidney disease (CKD) induces retention of water, sodium, and urea within the body, and is strongly related to the cardiovascular disease named uremic cardiomyopathy. Our previous study found that urea transporter (UT)-A protein was increased in hearts from CKD mice. We hypothesize that downregulation of UT-A could attenuate volume overload, which could be a new therapeutic strategy for uremic cardiomyopathy.

Methods

The CKD model was generated by uninephrectomy (Nx) in C57BL/6 wild-type (WT) and UT-A1/A3-/- (KO) mice. Blood pressure (BP) was determined by the tail cuff method. Echocardiography was performed on lightly anesthetized mice using the VisualSonics system. Heart tissue was harvested for protein and mRNA analysis by Western blot, histology and real-time PCR.

Results

BUN was 29.2 mg/dL (WT-sham), 52.3 mg/dL (WT-Nx), 26.3 mg/dL (KO-sham), and 55.1 mg/dL (KO-Nx), which proved the success of the CKD model. In WT mice, systolic BP (SBP) in Nx mice was higher than sham mice at 8 weeks; 92.5 mmHg vs 121.2 mmHg (P=0.0012), but not in KO mice; 102.0 mmHg vs 106.1 mmHg (P=0.128). The heart to brain weight ratio increased in WT mice (1.03 mg/mg (WT-sham) vs 1.18 mg/mg (WT-Nx); P=0.027), but showed no significant difference for KO mice. In KO-Nx mice, 24 hr urine volume increased (P=0.014) with decreased urine osmolality (P=0.029) compared with KO-shams, but WT-shams vs WT-Nx mice showed no differences. Echocardiography showed that ejection fraction decreased (57% vs 42%; P=0.0193) and left ventricular end-diastolic volume, which indicates preload, increased in WT-Nx mice vs WT-shams (53 μL vs 62 μL; P=0.0433). Gene expression of angiotensin converting enzyme was increased 1.26-fold in WT-Nx heart compared with WT-sham (P=0.0076), but showed no significant difference between KO-Nx and KO-sham.

Conclusion

Deletion of UT-A may reduce volume retention and suppress increased SBP and renin-angiotensin system activity that accompany CKD. UT-A inhibitors may be attractive diuretics for uremic cardiomyopathy.

Funding

  • NIDDK Support