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Abstract: FR-PO317

Tubulo-Glomerular Feedback Independent Hypertension and Kidney Interstitial Fibrosis in DOCA-Salt Mice

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Shi, Xiaoxiao, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Peng, Xiaoyan, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Tian, Dongli, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Xia, Peng, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Wen, Yubing, Peking Union Medical College Hospital, Beijing, BEIJING, China
  • Chen, Limeng, Peking Union Medical College Hospital, Beijing, BEIJING, China

Group or Team Name

  • Peking Union Medical College Hospital Kidney Lab
Background

Sodium transporters and tubulo-glomerular feedback (TGF) play important roles in sodium balance and blood pressure maintanence. Renal adenosine-A1 adenosine receptor (A1AR) pathway, which is mediated by Na-K-Cl cotransporter 2 (NKCC2), is involved in the classic TGF mechanism. This study was to observe the role of sodium transporters and A1AR in salt-sensitive hypertension and associated kidney injury.

Methods

Deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model was established by removal of left kidney, implantation of a DOCA pellet (200mg, 60-day release), and feeding with high salt diet (8%NaCl). Arterial blood pressure and urine electrolyte excretion were determined. Pathological changes, protein and mRNA expression of sodium transporters and adenosine-A1AR pathway were measured in mice kidney.

Results

DOCA-salt and uni-nephrectomy treatment in wildtype C57BL/6J mice led to continuous higher blood pressure, accompanied by obvious tubulo-interstitial injury and interstitial fibrosis at different ages (4w, 8w). In DOCA-salt wildtype mice, the Na+-Cl- cotransporter (NCC) and NKCC2 upregulation (1.6-1.75 times) were observed in kidney, with activation of adenosine-A1AR pathway (mRNA expression of adenosine synthetase CD73 and A1AR about 2-3 times increased). DOCA-salt mice also showed signs of glomerular hyperperfusion and hyperfiltration, which included polyuria, increased urine sodium excretion and kidney enlargement. Compared with DOCA-salt wildtype mice, the DOCA-salt A1AR-/- mice presented more severe glomerular hyperperfusion and hyperfiltration (including polyuria and increased urine sodium excretion). However, DOCA-salt A1AR-/- mice showed the same degree of hypertension (4w: 125.7±7.4 vs. 127.4±18.8 mmHg; 8w: 135.3±5.2 vs. 141.7±9.5 mmHg; P>0.05 both) and renal interstitial fibrosis (4w: 2.05±1.73% vs. 1.52±1.44%; 8w: 10.35±4.86 vs. 9.42±5.95%; P>0.05 both), which were compliant with the change of NCC protein expression (4w 1.65 ± 0.19 vs.1.70 ± 0.18; 8w 1.47 ± 0.21 vs 1.00 ± 0.34, P>0.05 both).

Conclusion

DOCA-salt treatment in mice induced hypertension and kidney interstitial fibrosis. The mechanism may lie in NCC activation, instead of NKCC2 associated TGF.

Funding

  • Government Support - Non-U.S.