# Animal models of salt sensitivity: roles of GRK4 and sodium transporters on salt sensitivity

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2020 · $746,799

## Abstract

The genetic causes of Na+ sensitivity of blood pressure (BP) are not well known. The kidney is critical to the
long-term regulation of fluid and electrolyte balance and BP. Thus, the pathogenesis of salt sensitivity must
involve a perturbation of renal Na+ handling. Salt-sensitive hypertension is associated with intronic variants of
the electrogenic NaHCO3 cotransporter gene (SLC4A5). Although Na+ load without Cl- may not elicit a pressor
effect, NaHCO3 can cause hypertension in some individuals but its pressor effect is less than NaCl. Hence, in
most cases of Na+-sensitive hypertension, there must be Na+ and Cl- retention. Essential hypertension is
associated with low serum HCO3-, implying an imbalance between renal Cl- and HCO3- transport. The renal
Na+/H+ exchanger type 3 (NHE3), Cl-/HCO3- exchanger, and NaHCO3 cotransporter are negatively regulated by
renal dopamine and positively regulated by angiotensin II. A disruption of these two systems may result in
hypertension with an imbalance of renal Cl- and HCO3- transport. Aberrant renal dopamine regulation of Na+
transport in hypertension can be caused by decreased expression or function of any of the five dopamine
receptors. The impaired function of dopamine receptors may be secondary to their constitutive desensitization
by G protein-coupled receptor kinase type 4 (GRK4), in the case of D1R and D3R. GRK4 variants (65L, 142V,
and 486V) are associated with hypertension and/or salt sensitivity. GRK4-65L, in particular, is also associated
with salt sensitivity in the cohort that we reported to have salt-sensitive hypertension associated with SLC4A5
variants. Human GRK465L (hGRK465L) transgenic mice are salt-sensitive and hGRK4-65L, alone or in
association with SLC4A5 intronic variants, increases the expression of SLC4A5, that may involve acetylation
(e.g., histone deacetylase 1, HDAC1), an instance of genetics regulating epigenetics which, in turn, then
regulates gene transcription (hGRK4, HDAC1, hepatocyte nuclear factor  [HNF4A]38a-c, and SLC4A5).
Project 3 will test the hypothesis that in some cases of salt-sensitive hypertension, hGRK465L and intronic
variants of SLC4A5 increase SLC4A5 expression in response to aberrant genetic regulation of epigenetic
pathways that also increase renal NHE3, NBCe2, and Cl-/HCO3- exchanger activities, The inter-regulation of
genetics and epigenetics plays a crucial role in the development of salt-sensitive BP.

## Key facts

- **NIH application ID:** 9949772
- **Project number:** 5P01HL074940-15
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Pedro A. Jose
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $746,799
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949772

## Citation

> US National Institutes of Health, RePORTER application 9949772, Animal models of salt sensitivity: roles of GRK4 and sodium transporters on salt sensitivity (5P01HL074940-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949772. Licensed CC0.

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