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We have recently demonstrated that intrarenal dopamine plays an important role in preventing the development of systemic hypertension. Similarly, renal cytochrome P-450 (CYP)-epoxygenase-derived arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs), also are antihypertensive through inhibiting sodium reabsorption and vasodilation. The potential interaction between renal dopamine and epoxygenase systems was investigated. Catechol-O-methyl-transferase (COMT)(-/-) mice with increased intrarenal dopamine levels and proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)) mice with renal dopamine deficiency were treated with a low-salt diet or high-salt diet for 2 wk. Wild-type or Cyp2c44(-/-) mice were treated with gludopa, which selectively increased renal dopamine levels. In low salt-treated mice, urinary EET levels were related to renal dopamine levels, being highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. In high salt-treated mice, total EET and individual EET levels in both the kidney and urine were also highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. Selective increases in renal dopamine in response to gludopa administration led to marked increases in both total and all individual EET levels in the kidney without any changes in blood levels. qRT-PCR and immunoblotting indicated that gludopa increased renal Cyp2c44 mRNA and protein levels. Gludopa induced marked increases in urine volume and urinary sodium excretion in wild-type mice. In contrast, gludopa did not induce significant increases in urine volume or urinary sodium excretion in Cyp2c44(-/-) mice. These studies demonstrate that renal EET levels are maintained by intrarenal dopamine, and Cyp2c44-derived EETs play an important role in intrarenal dopamine-induced natriuresis and diuresis.
The kidney has a local intrarenal dopaminergic system, and in the kidney, dopamine modulates renal hemodynamics, inhibits salt and fluid reabsorption, antagonizes the renin-angiotensin system, and inhibits oxidative stress. The current study examined the effects of alterations in the intrarenal dopaminergic system on kidney structure and function in models of type 1 diabetes. We studied catechol-O-methyl-transferase (COMT)(-/-) mice, which have increased renal dopamine production due to decreased dopamine metabolism, and renal transplantation was used to determine whether the effects seen with COMT deficiency were kidney-specific. To determine the effects of selective inhibition of intrarenal dopamine production, we used mice with proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)). Compared with wild-type diabetic mice, COMT(-/-) mice had decreased hyperfiltration, decreased macula densa cyclooxygenase-2 expression, decreased albuminuria, decreased glomerulopathy, and inhibition of expression of markers of inflammation, oxidative stress, and fibrosis. These differences were also seen in diabetic mice with a transplanted kidney from COMT(-/-) mice. In contrast, diabetic ptAADC(-/-) mice had increased nephropathy. Our study demonstrates an important role of the intrarenal dopaminergic system to modulate the development and progression of diabetic kidney injury and indicate that the decreased renal dopamine production may have important consequences in the underlying pathogenesis of diabetic nephropathy.
It is well-recognized that excessive angiotensin II (ANG II) can mediate progressive renal injury. Previous studies by us and others have indicated that dopamine may modulate actions of ANG II in the kidney. The current studies investigated whether altering intrarenal dopamine levels affected ANG II-mediated renal fibrosis. We utilized a model of increased intrarenal dopamine, catechol-O-methyl-transferase knockout (COMT KO) mice, which have increased kidney dopamine levels due to deletion of a major intrarenal dopamine-metabolizing enzyme. In wild-type mice, chronic ANG II infusion increased renal expression of both of the major dopamine-metabolizing enzymes, COMT and monoamine oxidase. After 8 wk of ANG II infusion, there were no significant differences in blood pressure between wild-type and COMT KO mice. Compared with wild-type, COMT KO mice had decreased albuminuria and tubulointerstitial injury. In response to ANG II infusion, there was decreased expression of both glomerular and tubulointerstitial injury markers (fibronectin, connective tissue growth factor, fibroblast-specific protein-1, collagen I, podocyte vascular endothelial growth factor) in COMT KO mice. We recently reported that ANG II-mediated tubulointerstitial fibrosis is mediated by src-dependent epidermal growth factor receptor (EGFR) activation. In aromatic l-amino acid decarboxylase knockout (AADC KO) mice, a model of intrarenal dopamine deficiency due to selective proximal tubule AADC deletion, which inhibits intrarenal dopamine synthesis, ANG II infusion further increased expression of p-src and pTyr845-EGFR. In contrast, their expression was markedly attenuated in COMT KO mice. These results demonstrate a role for intrarenal dopamine to buffer the detrimental effects of ANG II upon the kidney.
In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc-/- mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc-/- mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild-type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity.
Serotonin [5-hydroxytryptamine (5HT)] acts through multiple G protein-coupled 5-HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor-beta, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney.
Aromatic L-amino acid decarboxylase deficiency is an inborn error of metabolism that leads to combined serotonin and catecholamine deficiency, first described by Hyland et al in 1990. The clinical features, biochemical findings, and treatment of the second family with this condition are reported. Our male patient presented with developmental delay, extreme hypotonia, oculogyric crises, and irritability. The diagnosis of this inborn error of biogenic amine metabolism was accomplished by determining low concentrations of homovanillic, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenyl-ethyleneglycol in cerebrospinal fluid with normal biopterin metabolism and increased L-dopa, in plasma, cerebrospinal fluid, and urine. Greatly reduced activity of aromatic L-amino acid decarboxylase in plasma confirmed this diagnosis. Combined treatment with pyridoxine, tranylcypromine, and bromocriptine produced some clinical improvement.
Major strides in the molecular biology of essential hypertension are currently underway. This has tended to obscure the fact that a number of inherited disorders associated with low blood pressure exist and that these diseases may have milder and underrecognized phenotypes that contribute importantly to blood pressure variation in the general population. This review highlights some of the gene products that, if abnormal, could cause hypotension in some individuals. Diseases due to abnormalities in the catecholamine enzymes are discussed in detail. It is likely that genetic abnormalities with hypotensive phenotypes will be as interesting and diverse as those that give rise to hypertensive disorders.