DOPAMINE D4 RECEPTOR DOWN-REGULATES RENAL SODIUM CHLORIDE COTRANSPORTER VIA UBIQUITINATION-ASSOCIATED LYSOSOME...

Area of Science:

• Renal physiology and molecular biology
• Cardiovascular research
• Endocrinology

Background:

• The thiazide-sensitive sodium chloride cotransporter (NCC) is crucial for sodium reabsorption in the renal distal convoluted tubule (DCT), regulating blood pressure.
• Dopamine receptor D4 (Drd4) plays a role in a renal antihypertensive system, and its disruption causes hypertension, but the underlying mechanisms are unclear.

Approach:

• Investigated the effect of Drd4 deficiency and activation on NCC abundance and activity in mouse kidneys and cultured DCT cells.
• Utilized genetic manipulation (knockout mice, siRNA), pharmacological agents (agonists, antagonists, inhibitors), and biochemical assays (co-immunoprecipitation, FRET, Western blotting).

Key Points:

• Drd4 deficiency increased renal NCC protein levels and decreased NCC ubiquitination, correlating with hypertension.
• Drd4 activation promoted NCC internalization, lysosomal degradation, and reduced NCC-dependent sodium transport.
• Drd4 signaling involves the deubiquitinating enzyme USP48, which mediates NCC downregulation.

Conclusions:

• Dopamine receptor D4 (Drd4) negatively regulates the sodium chloride cotransporter (NCC) in the kidney.
• This regulation occurs through promoting USP48-associated deubiquitination, leading to NCC internalization, lysosomal degradation, and reduced activity.
• These findings elucidate a novel mechanism linking Drd4 signaling to blood pressure regulation via NCC modulation.