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,**,3
* Nephrology Section VA Medical Center,
Renal Division and
** Vascular Biology Institute, University of Miami School of Medicine, Miami, FL 33136
3To whom correspondence should be addressed. E-mail: ejaimes{at}med.miami.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • L-arginine • kidney failure • glomerulonephritis • hypertension • preeclampsia • nitric oxide
L-arginine is a semi essential amino acid and is also substrate for the synthesis of nitric oxide (NO),4 polyamines, and agmatine and influences hormonal release and the synthesis of pyrimidine bases (1,2). This places L-arginine, its precursors, and its metabolites at the center of the interaction of different metabolic pathways and interorgan communication.
L-arginine is the main source for the generation of NO via NO synthase (NOS) (2). Approximately 1% of the daily L-arginine intake is metabolized through this pathway (3). The 3 NOS isoforms have been found to be expressed in the kidney (2). In the kidney the endothelial NOS (eNOS) is important in the maintenance of glomerular filtration rate, regional vascular tone, and renal blood flow (4). The neuronal NOS (nNOS) is expressed primarily in the macula densa and participates in the control of glomerular hemodynamics via tubulo-glomerular feedback and renin release (4). The inducible NOS (iNOS) is expressed in the kidney under pathological conditions in the glomerular mesangium, infiltrating macrophages and tubules (4). Expression of iNOS has also been reported in specific tubular segments but its physiological significance remains unclear (5).
L-arginine is also the substrate for arginases, a group of enzymes that are involved in tissue repair processes and that metabolize L-arginine to L-ornithine (6). Arginase I is expressed in the liver while arginase II is expressed in the kidney and macrophages (6). L-ornithine is the first step in the synthesis of the polyamines putrescine, spermine, and spermidine via the enzyme ornithine decarboxylase (7). Increased activity of this enzyme has been associated with tissue repair and cell growth (1) and may play an important role in renal disease (8).
More recently another L-arginine metabolizing pathway has been identified. This pathway involves the generation of agmatine via the enzyme L-arginine decarboxylase (ADC) (9). Agmatine can activate 
-1 adrenoreceptors and imidazol-guanidine receptors (9) and when infused into the renal interstitium increases glomerular filtration and tubular reabsorption (10). ADC activity is high in the normal kidney (11) and therefore it is possible that agmatine may be mediating some of the biological effects of L-arginine supplementation in renal disease.
All the above-mentioned L-arginine metabolites may participate in pathogenesis of renal disease and constitute the rationale for manipulating L-arginine metabolism as a strategy to ameliorate kidney disease. A large number of studies have been performed in experimental models of kidney disease with sometimes conflicting results, which underlie the complexity of L-arginine metabolism and our incomplete knowledge of all the mechanisms involved.
L-arginine in chronic kidney disease
Beneficial effects of L-arginine supplementation have been reported in several models of chronic kidney disease (CKD) including renal ablation, ureteral obstruction, puromycin induced nephrosis and nephropathy secondary to diabetes, salt sensitive hypertension, radiocontrast agents, and aging (12–21).
In the remnant rat model of CKD, a decrease of 85 to 90% of the total kidney mass results in a series of functional changes including increases in single nephron glomerular filtration rate (SNGFR), progressive reductions in glomerular filtration rate (GFR) and renal plasma flow (RPF), hypertension, proteinuria and structural changes including epithelial cell protein reabsorption droplets, foot process fusion, mesangial expansion, and progressive glomerulosclerosis (22,23). In this model, the renal synthesis of NO decreases in parallel with the decline of renal function (24). Based on this observation, L-arginine supplementation has been used as a strategy to ameliorate the progression of kidney disease in this model. Administration of L-arginine in the drinking water for 6 wk to rats with subtotal nephrectomy resulted in higher GFR and RPF compared to their untreated counterparts (12). L-arginine–treated rats also had a larger number of normal or minimally abnormal glomeruli and also had less severe tubulointerstitial changes. Importantly, these beneficial effects of L-arginine were independent of blood pressure or protein intake.
Other studies have also shown similar effects in a similar model of remnant kidneys but utilizing L-arginine supplementation at a dose approximately one tenth of that used in the above-mentioned studies (20). In these studies, L-arginine supplementation had beneficial effects equivalent to those of angiotensin converting enzyme (ACE) inhibition with captopril including reductions in proteinuria, increase in GFR and increase in the urinary excretion of the stable NO metabolites NO2/NO3.
Bilateral ureteral obstruction (BUO) is another model of chronic kidney disease characterized by low GFR and RPF, interstitial fibrosis, hypertension, leukocyte infiltration, and increased tubular apoptosis (25,26). Increased eNOS and iNOS expression (27) and low plasma levels of L-arginine (28) have been reported to occur in this animal model. Administration of L-arginine in the drinking water to rats with BUO ameliorates the decreases in GFR and elevations of blood pressure in these rats (28) and is associated with increased urinary NO2/NO3 excretion (29) and significant reductions in interstitial volume, monocyte infiltration, and collagen IV deposition (17). Based on these findings it has been postulated that reduced NO synthesis, because of decreased availability of substrate and in spite of increased eNOS and iNOS expression, may be playing a pathogenic role in this model of kidney disease.
The effects of L-arginine administration on the renal function of untreated diabetic rats have also been examined (16). L-arginine administration in the drinking water of diabetic rats reduced the urinary excretion of cyclic GMP (cGMP), prevented the development of hyperfiltration and significantly reduced proteinuria (16). The mechanisms involved were not investigated.
The Dahl salt sensitive (DS) rat is a paradigm of low plasma renin, salt sensitive hypertension (30). DS rats downregulate eNOS and develop impaired NO-mediated endothelial function, accompanied by cardiovascular and renal injury. Recent studies support the notion that salt sensitive hypertension might represent a vascular diathesis linked to functional upregulation of angiotensin II (Ang II) actions, accompanied by insufficient NO bioavailability and increased oxidative stress (31). Ang II activates NADH/NADPH oxidase in endothelial cells, vascular smooth muscle cells, adventitial fibroblasts, and glomerular mesangial cells (32). NADH/NADPH oxidase in turn produces superoxide anion (O2–), which avidly interacts with NO, reduces its bioactivity, and generates peroxynitrite (33). Renal expression of NADH/NADPH oxidase has been found to be increased in hypertensive salt loaded DS rats and associated with increased production of superoxide anion and decreased NO bioactivity (31).
In hypertensive Dahl/Rapp rats the administration of L-arginine but not of D-arginine results in significant reductions in blood pressure and increases the urinary excretion of cGMP (34). More recent studies in hypertensive DS rats have shown that supplementation with L-arginine increases plasma NO2/NO3 and produces significant reductions in blood pressure, renal NADH/NADPH oxidase expression, proteinuria, and superoxide anion production (35). These effects of L-arginine suggest that in the hypertensive DS rat there is a reduction in the availability of L-arginine that may be responsible at least in part for the increases in oxidative stress and reductions in NO bioavailability that play an important role in the pathogenesis of renal injury in this model.
L-arginine supplementation has also been investigated in the DOCA-salt hypertensive rat, a model of severe hypertension accompanied by severe renal injury. In this model L-arginine supplementation for 8 wk (0.5 g/L in drinking water) was shown to improve endothelial function and increase the renal production of NO (36). These changes were not associated with improvements in glomerular injury or the severity of hypertension (36). However, other studies utilizing higher doses of L-arginine (3 g · kg–1 · d–1) for 6 wk have reported significant reductions in blood pressure in the same animal model (37).
L-arginine in glomerular diseases
One of the central characteristics of immune-mediated renal injury is the local induction of iNOS resulting in the production of large amounts of NO. iNOS induction has been demonstrated in a variety of models including anti-thymocyte-serum (ATS) induced glomerulonephritis, immune-complex glomerulonephritis, and transplant rejection (8,38–40). In human renal disorders, increased expression of iNOS mRNA and protein has been documented in mesangioproliferative glomerulonephritis (41), Wegener’s granulomatosis (42), lupus nephritis (43), and kidney transplant rejection (44) and correlated with histologic signs of renal damage and loss of renal function. The ATS model is a rat model of mesangial proliferative glomerulonephritis induced by the injection of an antibody to a Thy 1-like epitope that causes dose-dependent complement mediated glomerular injury (45). This model is characterized by initial mesangiolysis followed by mesangial cell proliferation and accumulation of mesangial matrix with subsequent resolution and the return to almost normal histology (45). In ATS glomerulonephritis, NOS inhibition before ATS administration produces a dramatic reduction in mesangial cell lysis, which implies that increased NO production may play an important pathogenic role at least in the injury phase of this model (46). Moreover, supplementation with 1% L-arginine in the drinking water during the induction phase of ATS glomerulonephritis results in significant increases in glomerular NO production, increased proteinuria and fibrosis (38), suggesting that in this model, L-arginine supplementation can enhance NO-dependent tissue injury by providing increased substrate for iNOS. In support of this notion, restriction of dietary L-arginine intake in the same model, even when total protein intake is normal, results in decreased proteinuria, decreased expression of transforming growth factor-ß (TGF-ß), and decreased extracellular matrix deposition, indicating that dietary L-arginine restriction may be limiting the substrate for NO generation and via this mechanism limiting glomerular injury (47). In contrast, when L-arginine is administered after the injury phase is completed, it results in significant reductions in extracellular matrix accumulation, TGF-ß expression, and fibrosis, suggesting that NO may have a role regulating TGF-ß overexpression during the fibrotic phase of this model of glomerulonephritis (48).
In contrast with ATS glomerulonephritis, in experimental immune-complex glomerulonephritis increased NO generation via iNOS induction does not seem to promote glomerular injury (49,50). In a model of nephritis induced by administration of nephrotoxic globulin to preimmunized rats, L-arginine depletion via systemic administration of arginase worsened the severity of the glomerular injury especially if hypertension was present, suggesting that rather than favoring tissue injury, NO may have a role limiting the magnitude of glomerular injury in this model (49). Moreover, in a mouse model of accelerated anti-glomerular basement membrane glomerulonephritis (anti-GBM), genetic disruption of iNOS did not result in significant changes in albuminuria or glomerular inflammation compared with their heterozygous littermates, indicating that iNOS does not play an essential role in this form of glomerulonephritis in the mouse (51).
L-arginine supplementation has also been used in models such as the lupus nephritis in MRL/lpr mice, a model of chronic and progressive glomerulonephritis in which glomerular iNOS expression and activity are increased (52). In this model, administration of 1% L-arginine in the drinking water was associated with a high death rate, increased albuminuria, extracellular matrix accumulation, TGF-ß expression, and blood and urine NO2/NO3 levels, suggesting that L-arginine worsens renal fibrosis and increases death rate probably by enhancing cytotoxic NO generation via iNOS (53).
A few clinical studies have also investigated the effects of L-arginine supplementation on the progression of nondiabetic glomerular disease with disappointing results. Oral administration of L-arginine (0.2 g · kg–1 · d–1) for 6 mo to subjects with different types of glomerulonephritis resulted in significant increases in the plasma levels of L-arginine and a delayed increase in the plasma levels of the stable NO metabolites NO2/NO3, but no change in proteinuria, glomerular filtration rate, and renal plasma flow compared to a control group receiving placebo (54). In another study, L-arginine supplementation for 8 wk in patients with chronic rejection led to significant increases in plasma levels of L-arginine that were not associated with changes in renal function or peripheral vascular disease (55).
L-arginine in acute renal failure
Acute renal failure (ARF) is a common clinical condition associated with a high morbidity and mortality (56). Multiple strategies including L-arginine supplementation have been attempted to ameliorate the course of ARF. In several studies administration of exogenous L-arginine has been shown to protect the kidney against toxic or ischemic injury (57–60). However, the molecular mechanisms for these beneficial effects are unclear and occur even though the intrarenal levels of L-arginine are well above the Km value for NOS saturation of 3 to 5 µmol/L (61). This phenomenon has been described as the "L-arginine paradox" (62).
Defects in the L-arginine:NO pathway have been proposed to play an important role in the pathogenesis of ARF (63,64). Several studies have suggested that NO bioactivity is reduced in models of postischemic ARF as assessed by a blunted response to endothelium-dependent vasodilators such as acetylcholine and bradykinin (65–67) and increased constrictor responses to renal nerve stimulation (66) and Ang II. Interestingly, these reductions in NO bioactivity are accompanied by increases in iNOS expression and activity (68) and in the case of eNOS there was either no change in its expression (65) or a transitory increase followed by a reduced expression (68).
In models of ischemic ARF these changes in iNOS expression are accompanied by increased production of superoxide anion and peroxynitrite (ONOO–) leading to nitrosative stress. Nitric oxide rapidly reacts with O2– resulting in the generation of the highly reactive ONOO– and reduced NO bioactivity. ONOO– itself can produce lipid peroxidation and DNA damage and in addition can produce NOS uncoupling by affecting the NOS dimeric structure. Increased O2– production has been found in several models of ischemic ARF. Among the potential sources of O2– in the kidney are NADPH oxidase, xanthine oxidase, or uncoupled NOS. In addition, reduced expression of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase, and catalase may also contribute to increase oxidative stress in ischemic ARF (69). Inhibition of iNOS has been shown to be beneficial in models of ischemia reperfusion, which suggests that increased iNOS expression and activity may have roles in the pathogenesis of ischemic ARF (70). In contrast, NOS inhibition during endotoxemia results in glomerular thrombosis suggesting that increased iNOS activity may also have a protective role under specific conditions (71,72).
Exogenous L-arginine supplementation for 14 d in a model of ischemic acute renal failure has been shown to have a beneficial effect on GFR, RPF, reduced O2– production and prevention of iNOS upregulation as well as reduced nitrotyrosine formation. These beneficial effects may suggest a functional NO deficiency in ischemic ARF, probably as a result of inactivation by O2– and subsequent ONOO– generation. Decreased renal L-arginine production has been found to occur in models of renal ischemia/reperfusion that may be contributing to the reductions in the tissue levels of L-arginine observed in ARF (60). Although reduced, these levels are still well above the Km for NOS, which suggests that other cytoprotective mechanisms may be involved (73). As an alternative explanation for these beneficial effects, it has been suggested that L-arginine compartmentalization in the cytoplasm may result in lower levels of L-arginine in the vicinity of eNOS and a relative L-arginine deficiency in spite of appropriate tissue or plasma levels of L-arginine (74). As an alternative explanation, it has also been suggested that L-arginine excess may be beneficial by overcoming the activity of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) which has been reported to be increased in renal failure (75). In addition, a relative L-arginine deficiency may lead to NOS uncoupling (76), as has been described for tetrahydrobiopterin (BH4), leading to the production of O2– instead of NO by NOS. This mechanism could explain the lowered renal production of O2– in models of ARF treated with L-arginine.
L-arginine in preeclampsia
Pre-eclampsia occurs in aproximately 5 to 10% of all pregnancies in the United States and is a significant cause of maternal and fetal morbidity and mortality (77). Clinically pre-eclampsia presents as increased responsiveness to vasoconstrictors, elevations in arterial pressure, proteinuria, reduced glomerular filtration rate, and intrauterine growth retardation (78). It has been suggested that reduced placental perfusion leading to maternal endothelial dysfunction may play a critical role as an initiating event in preeclampsia (79). Strong clinical and experimental evidence suggests that NO production is elevated in normal pregnancy and significantly contributes to gestational vasodilation (80,81). In the rat, plasma and urinary levels of cGMP and levels of urinary NO2/NO3, metabolites of NO, are increased during pregnancy (81–83). Endothelial NOS has been found to be present in healthy placenta and is localized to the endothelium of the umbilical cord, chorionic plate, and stem villous vessels (84). Locally produced NO may be helping to maintain low vascular resistances besides attenuating the action of vasoconstrictors. In addition increased renal expression of iNOS and nNOS has been found in rat midgestation (82).
Several studies have shown that chronic inhibition of NO synthesis during pregnancy in the rat results in the development of many of the preeclamptic features, including elevations in blood pressure, reductions in GFR, proteinuria, and intrauterine growth retardation (85,86), that are reversible by the administration of L-arginine (86,87) and therefore suggestive of a role for reduced NO production in the pathogenesis of preeclampsia. In addition, reductions in uterine perfusion pressure in pregnant rats results in responses similar to those observed after inhibition of NO synthesis in pregnant rats including hypertension, proteinuria, and intrauterine growth retardation (88). Moreover, the levels of cGMP, the NO second messenger, are reduced in rats with reduced uterine perfusion pressure (89). In this model significant reductions in renal nNOS protein expression in late gestation compared with the late-gestational in control rats (88) have been observed. However, recent studies in women with preeclampsia have suggested that placental eNOS expression and activity are comparable during normotensive pregnancy and preeclampsia (90), suggesting that increased NO inactivation by reactive oxygen species (ROS) or NOS uncoupling may be playing a role in the development of endothelial dysfunction of preeclampsia. In support of this hypothesis, the levels of peroxynitrite were increased in the villi of placentas from preeclamptic women compared to those from women with normal pregnancy (90). Increased tissue levels of nitrotyrosine are strong indicators of increased oxidative stress resulting in the generation of the highly reactive peroxynitrite as a consequence of the interaction of NO with O2–. Increased oxidative stress may be secondary to increased activity of enzymes responsible for the production of ROS, or alternatively as a result of NOS uncoupling redirecting NOS towards the production of ROS instead of NO. NOS uncoupling can occur as a result of reductions in NOS cofactors such as BH4 or reductions in L-arginine (76). In support of the latter the level of L-arginine in the umbilical cord and villous tissue was significantly reduced in preeclampsia compared to normotensive pregnancy (90). These reductions in L-arginine were found to be due to lower activity of arginase, the enzyme that degrades arginine to ornithine, in preeclamptic villi than in normotensive pregnancy (90). In support of a role for reduced L-arginine levels in the pathogenesis of preeclampsia, a recent study showed that L-arginine supplementation resulted in a significant decrease in arterial pressure in both pregnant rats with reduced uterine perfusion pressure and pregnant control rats (91). Supplementation with L-arginine decreased blood pressure by 19 mm Hg in pregnant rats with reduced uterine perfusion pressure compared with 12 mm Hg in control pregnant rats and was accompanied by increased urinary excretion of the stable NO metabolites NO2/NO3. This study further supports the notion that L-arginine supplementation may be beneficial in attenuating hypertension in preeclampsia.
Animals (92,93) and humans (94) are known to be more susceptible in late pregnancy to develop glomerular thrombosis and renal failure due to pathologic processes that result in endothelial injury and increased blood coagulability. In humans these processes include preeclampsia, the HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelet count), and septic abortion (95) and in rodents such as the rabbit and the rat endotoxin administration results in glomerular thrombosis if given close to the time of delivery (92,93,96). Pregnant rats given 0.75 mg/kg of lipopolysaccharide (LPS) develop glomerular thrombosis in 75% of the glomeruli and results in 98% reductions in the plasma levels of L-arginine, but the urinary NO2/NO3 levels did not change (96). In contrast the same dose of LPS results in a decrease of only 40% in virgin rats and an increase in urinary NO2/NO3 levels by 200% (96). Oral administration of L-arginine but not D-arginine increased urinary NO2/NO3 levels by 250% and averted glomerular thrombosis in pregnant rats with LPS, which suggests that limited maternal reserve capability for NO synthesis may underlie the susceptibility for glomerular thrombosis in pregnancy (96).
Summary
Experimental evidence supports both a beneficial as well as a deleterious role for L-arginine in the pathogenesis of specific models of renal disease. L-arginine seems to promote renal injury in some models of glomerulonephritis including ATS glomerulonephrits and lupus nephritis. In contrast, L-arginine seems to be beneficial in experimental models of acute renal failure as well as in models of chronic renal disease such as renal ablation and ureteral obstruction. L-arginine also ameliorates renal injury in animal models of preeclampsia as well as in some models of hypertensive renal injury. Unfortunately only a few clinical trials have been carried out with disappointing results. Additional experimental and clinical studies are needed to better understand the role of L-arginine in the pathogenesis and treatment of renal disease.
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FOOTNOTES |
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2 Funding from Merit Review Award of the Veterans Affairs Administration provided to Edgar A. Jaimes.
4 Abbreviations used: ADC, L-arginine decarboxylase; Ang II, angiotensin II; ARF, acute renal failure; BH4, tetrahydrobiopterin; BUO, bilateral ureteral obstruction; cGMP, cyclic GMP; CKD, chronic kidney disease; DS, Dahl salt sensitive; eNOS, endothelial NOS; GFR, glomerular filtration rate; iNOS, inducible NO synthase; LPS, lipopolysaccharide; nNOS, neuronal NOS; NO, nitric oxide; NOS, nitric oxide synthase; O2–, superoxide anion; ONOO–, peroxynitrite; RPF, renal plasma flow; ROS, reactive oxygen species; TGF-ß, transforming growth factor-ß.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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