Acute infusion of angiotensin II regulates organic cation transporters function in the kidney: its impact on the renal dopaminergic system and sodium excretion

In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.

LAT1 and LAT2 are heterodimeric large amino acid transporters that are expressed in various tissues, including the intestinal wall, blood-brain barrier, and kidney. These transporters consist of membrane spanning light chain and heavy chain, and they act as 1:1 exchangers in concert with other amino acid transporters. Only a few drugs (less than 10) are substrates of LAT1 and LAT2, including L-DOPA, alpha-methyldopa, melphalan, and gabapentin. The mechanisms and substrates have been mostly elucidated using mammalian cells and Xenopus oocytes. The in vivo relevance of LAT1 and LAT2 in pharmacokinetics is obscure, because contradictory findings have been reported. It is difficult to make quantitative pharmacokinetic conclusions about LAT1 and LAT2. This is due to the possible involvement of other transporters (including cross-linked heterodimers of light chain with different heavy chains, other overlapping transporters, for example TAT1), competing endogenous amino acids, and saturation phenomena. This review presents the current functional knowledge on LAT1 and LAT2 with emphasis on their potential involvement in pharmacokinetics.

For the elimination of environmental toxins and metabolic waste products, the body is equipped with a range of broad-specificity transporters that are generally present in the liver, kidney, and intestine. The polyspecific organic cation transporters OCT1, 2, and 3 (SLC22A1-3) mediate the facilitated transport of a variety of structurally diverse organic cations, including many drugs, toxins, and endogenous compounds. OCT1 and OCT2 are found in the basolateral membrane of hepatocytes, enterocytes, and renal proximal tubular cells. OCT3 has a more widespread tissue distribution and is considered to be the major component of the extraneuronal monoamine transport system (or uptake-2), which is responsible for the peripheral elimination of monoamine neurotransmitters. Studies with knockout mouse models have directly demonstrated that these transporters can have a major impact on the pharmacological behavior of various substrate organic cations. The recent identification of polymorphic genetic variants of human OCT1 and OCT2 that severely affect transport activity thus suggests that some of the interpatient differences in response and sensitivity to cationic drugs may be caused by variable activity of these transporters.