8. Renal dopaminergic system

The Renal dopaminergic system. Dopamine not only serves as a neurotransmitter in the central nervous system, it is also an essential endogenous modulator of sodium homeostasis, redox balance and blood pressure in the kidney (PMID: 25949933).
The kidney has all the bioenzymatic machinery necessary to possess a local dopaminergic system. L-DOPA, the dopamine precursor, is filtered at the glomerulus and is taken up by the proximal tubule via several luminal transporters, mainly LAT1 (SLC7A5) and LAT2 (SLC7A8) (PMID: 22169008). Alternatively, tyrosine is converted in the kidney to L-DOPA via tyrosine hydroxylase (TH) (PMID: 30808844). L-DOPA is further carboxylated to dopamine via dopa decarboxylase (DDC) (PMID: 2594993).
The effects of dopamine are exerted via five receptors, D1 to D5, encoded by the genes DRD1 to DRD5, that can be divided into two sub-classes: D1-like receptors (D1, D5) and D2-like receptors (D2, D3, D4) (PMID: 33255376). By activation of these receptors, dopamine increases renal blood flow and elicits a marked natriuretic response by its capacity to inhibit sodium transporters (e.g. Na+/K+ ATPase, Na+/H+ exchanger (SLC9A3) (PMID: 30808844). In addition, dopamine regulates ROS production, either by down-regulation of NADPH oxidase activity, or by stimulating anti-oxidants such as paraoxinase 2 (PON2) or heme-oxygenase (HMOX) necessary to counterbalance the adverse effects of oxygen free radicals (PMID: 25436148). Dopamine also attenuates renal inflammation by inhibiting NLRP3 inflammasome activity or by downregulation of inflammatory factors such as TNF or MCP1 (CCL2) (PMID: 22719934). Besides these direct effects, dopamine exerts its effects also indirectly by interacting with other hormonal factors (PMID: 32349533). Intrarenal dopamine counteracts renal effects of the renin-angiotensin system (AGTR1, AGTR2, REN) (PMID: 21701066) and synergistically induces sodium excretion together with the intestinal gastrin (PMID: 24019399).
Essential hypertensive patients have lower urinary dopamine levels than normotensive subjects. Diabetic patients have a decreased renal dopamine production, and insulin stimulates L-DOPA uptake into renal proximal cells. Low levels of dopamine are also associated with the progression of diabetic nephropathy. (PMID: 23733636)

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