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Abstract: TH-OR002

The Hypertension Induced by Renal Snx5 Silencing Is Associated with Increased Renal Protein Abundance of NHE3, NaPi2, NKCC2, and NCC in Mice

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Author

  • Yu, Yanting, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background

Sorting nexin 5 (SNX5) plays an important role in the function of renal dopamine receptor subtype 1 (D1R). The gene silencing of renal Snx5 by its siRNA decreases renal D1R but increases blood pressure (BP) in rats; it also decreases renal expression of insulin receptor and insulin degrading enzyme and causes insulin resistance in mice.

Methods

In order to test the hypothesis that SNX5 deletion affects renal sodium absorption and develops hypertension, we measured BP, water and sodium balance, and renal protein expression of sodium transporters in C57BL6/J mice treated with siRNAs of SNX5 or mock. 8 male C57Bl6 mice (5-6 months old) were uninephrectomized 3 weeks prior to the infusion of SNX5-siRNA or mock-siRNA (3 mg/kg.day, n=4/group) via osmotic mini-pump into sub-capsular space for 1 week.

Results

In SNX5-siRNA-treated mice, systolic (119±5.2, mm Hg, under anesthesia) and diastolic BPs (91.8±7.3) were elevated, relative to mock-siRNA-treated mice (SBP=101.5±0.5, DBP=72±2.3). Food and water intake, body weight, urine volume and heart rate were similar in the two groups. The gene silencing decreased the protein expression of SNX5 and D1R by 70% and 30% respectively (immunoblotting). In control mice, SNX5 and D1R colocalized mainly in the apical membrane of the proximal tubules, thick ascending limbs of loop of Henle, but not in collecting ducts. The two proteins also co-immunoparticipated in mouse kidney homogenates and cell lysates from cultured mouse proximal tubule cells. The gene silencing of Snx5 increased renal protein expressions of NHE3 (172±30, % of control), NaPi2 (223±12), NKCC2 (286±54), NCC (177±23), but did not alter the protein expressions of ENaCs and Na+K+ATPase.

Conclusion

These findings suggest that inhibition of SNX5 by siRNA increases the apical sodium transporters in proximal and distal nephron segments, in which SNX5 and D1R were co-localized. This may cause the impaired sodium excretion that may be responsible for the increased blood pressure in SNX5-siRNA-treated mice.

Funding

  • Other NIH Support