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Abstract: FR-PO954

Molecular Mechanisms Underlying the GRK4 65L-Mediated Hypertension in Mice

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Rozyyev, Selim, George Washington University, Washington, District of Columbia, United States
  • Konkalmatt, Prasad, George Washington University, Washington, District of Columbia, United States
  • Villar, Van Anthony M., George Washington University, Washington, District of Columbia, United States
  • Asico, Laureano D., George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
  • Kumar, Megha, George Washington University, Washington, District of Columbia, United States
  • Jose, Pedro A., George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States
  • Armando, Ines, George Washington University, Washington, District of Columbia, United States
Background

The genetic causes of salt sensitivity and hypertension in humans are not completely understood. The kidney plays a preeminent regulatory role in water and electrolyte balance and blood pressure (BP) homeostasis. The renal dopamine receptors, D1R and D3R, engender natriuresis via the inhibition of renal Na+ transport, whereas the angiotensin II type 1 receptor (AT1R) does the opposite. The renal paracrine inhibition of Na+ transport by dopamine is impaired in salt-sensitive rats, mice, and humans. Agonist activation promotes the phosphorylation of D1R and D3R by the G protein-coupled receptor kinase type 4 (GRK4), whose gene variants impair D1R and D3R activity.

Methods

To demonstrate the specific renal causal mechanisms in GRK4 65R>L-mediated hypertension, we heterologously expressed the GRK4 65R>L vs. GRK4 wild-type (WT) transgenes in the kidneys of Grk4 knockout mice on normal salt diet. The transgenes were delivered selectively into the renal tubules by the bilateral retrograde ureteral infusion of AAV-9 vectors.

Results

The renal tubule-restricted expression of GRK4 65R>L increased the BP (117±4 vs. 93±1 mm Hg, P<0.05, n=4), while that of the GRK4 WT only tended to increase the BP (105±6 vs. 96±2 mm Hg, n=5), indicating that the presence of the GRK4 variant in the kidney caused the increase in BP. We next evaluated the renal expression profiles of select genes. We found that the expressions of the pro-natriuretic D1R (0.81±0.01 vs. 1.28±0.04, P<0.01) and D3R (0.44±0.02 vs. 1.27±0.07, P<0.01) were decreased. By contrast the expressions of the anti-natriuretic Na+/K+-ATPase (1.14±0.024 vs. 1.0 ±0.007, P<0.05) and a-ENaC (1.4±0.14 vs. 1.0±0.11, P<0.05) were increased, demonstrating the mechanistic changes that underlie the hypertension in these mice. Interestingly, we also observed that the expressions the AT1R (0.82±0.02 vs. 1.02±0.02) and the proximal tubule Na+ transporters NaPi2 (0.81±0.02 vs. 1.04±0.02), SGLT2 (0.89±0.03 vs. 1.07±0.05), and NBCe2 (0.50±0.07 vs. 1.15±0.03), were decreased, which may represent insufficient compensatory mechanisms against the increase in BP

Conclusion

Our results highlight the underlying and compensatory renal mechanisms for the hypertension that developed in mice with either kidney-restricted or globally expressed GRK4 65R>L.

Funding

  • NIDDK Support