Nitric Oxide

Guanidinobutyraldehyde

Fig. 2. Arginine pathways. In acute inflammatory models, (A) arginine to nitric oxide (NO) production is an early phase response. NO is an antiproliferative molecule resulting, to some degree, from nitrosylation and inactivation of ornithine decarboxylase (ODC). (B) The production of ornithine and subsequent metabolism to the pro-proliferative polyamines (ODC) and to proline (OAT) for extracellular matrix production is a later repair phase response. Agmatine induction of antizyme and SSAT can aid in the regulation of intracellular polyamine levels in normal cell homeostasis, in part by adding to the free polyamine pool. Induction of amine oxidase metabolizes agmatine to a moiety that selectively inhibits inducible nitric oxide synthase (iNOS). Suppression of iNOS also occurs by several other factors released during inflammation, such as cytokines. Besides suppressing iNOS, the metabolism of agmatine would shift its repression away from the polyamines and be permissive for growth in the repair phase. Bars represent negative regulation. ADC, arginine decarboxylase; AO, amine oxidase; OAT, ornithine aminotransferase; SSAT, acetyl CoA:Spd/Spm #-acetyltransferase.

Thy-1-mediated glomerulonephritis affords a model to evaluate experimental perturbations in these arginine pathways. After an early onset of iNOS induction and NO generation, increases in arginase, ODC, and OAT correlate with the repair phase (i.e., cell proliferation and collagen synthesis) of the response (41). Inhibition of NOS by N(G)-monomethyl-L-arginine (L-NMMA) administration in experimental glomeru-lonephritis increases both the magnitude and onset of the repair phase response (28), indicating competition for substrate by the two enzymes, or interregulation of these two pathways by NO. Competition for arginine by these enzymes is well documented in other models (42). However, in the Thy-1 model, iNOS and arginase activities are observed in different cell types—macrophage and mesangial cells, respectively— thereby effectively limiting competition. NO can directly nitrosylate and inhibit ODC activity (29). Nitrosylation is readily reversible and dependent on the oxidative state of the cell. It becomes more prevalent when oxidative stress compromises intracellular thiol levels, as mentioned previously in Subheading 4.1.

DFMO administration in the Thy-1 model successfully inhibits ODC activity but had no effect on mesangial cell hyperplasia, glomerular matrix protein expression, or albuminuria (43). This may be owing to a compensatory polyamine uptake mechanism. Agmatine was effective in this Thy-1 model in reducing ODC activity, hyperplasia, and matrix formation and preventing the decline in GFR (44). A direct effect of agmatine administration on iNOS activity was not statistically significant in these experiments, even though the decline in GFR was eliminated during the initial "NO" phase. This was likely the result of the very indirect technique of measuring NO generation ex vivo and should be reevaluated.

4.3. Lupus

Systemic lupus erythematosus (SLE) is an immune disorder characterized by numerous autoantibodies. The kidney is involved in virtually all cases of SLE. It can manifest as mesangial lupus glomerulonephritis, focal proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, or membranous glomerulonephritis. Glomerulonephritis is a major cause of morbidity and mortality in SLE. The MRL lpr/lpr mouse model produces chronic and progressive glomerulonephritis. Administration of arginine in the drinking water of MRL lpr/lpr mice was associated with increased blood and urine NO levels, albuminuria, extracellular matrix accumulation, and mortality, even though anti-ds DNA-immunoglobulin (Ig)A and renal Ig deposition did not change with the treatment 45). In accord with these data, DFMO administration has proven quite effective in this model. MRL lpr/lpr mice administered DFMO demonstrated lower anti-DNA antibodies (46), decreased interstitial inflammation, perivascular inflammation, vasculitis, and glomerulonephritis (47), with a resultant increase in mean survival time (46-48). These findings were verified in a different genetic background in lupus-prone NZB/W mice in which DFMO treatment also decreased anti-DNA antibody by approx 80% with resultant decreases in proteinuria and blood urea nitrogen (BUN) levels (49). ODC activity is elevated in MRL lpr/lpr mice, as expected from the DFMO results, but ODC mRNA is decreased suggesting posttranscriptional regulation of the enzyme (48).

5. Chronic Kidney Disease

Chronic renal failure is the end result of a variety of kidney diseases. It is the major cause of death from renal disease. The route to chronic renal failure advances through several stages demarcated by progressive decreases in GFR. The first stage, diminished renal reserve, denotes a GFR approx 50% of normal. The patients are asymptomatic, with normal serum BUN and creatinine levels, attesting to the large reserve of the kidney before damage affects health. Renal insufficiency is when the GFR is 20 to 50% of normal, with azotemia (an increase in BUN and creatinine levels), polyuria, and nocturia. It is usually associated with anemia and hypertension. Renal failure occurs when the GFR drops below 20-25% of normal. At this stage, the kidneys cannot regulate properly. Chronic kidney disease is associated with edema, metabolic acidosis, and hypocalcemia. The terminal stage of uremia, in which the GFR drops below 5%, is end-stage renal disease.

5.1. Remnant Kidney Model

The remnant kidney model comprises a 5/6 nephrectomy (or more), which institutes renal insufficiency and uremia. There is an increase in single nephron GFR commensurate with the amount of renal mass ablated. This hypertrophic response is considered beneficial as it attempts to minimize the decline in total GFR and renal plasma flow.

Yet, unlike compensatory hypertrophy in the unilateral nephrectomy model, disease is progressive and relentless. It is accompanied by hypertension, proteinuria, and progressive glomerulosclerosis. Endothelial cells show membranous whorls and lifting, epithelial cells show protein reabsorption droplets associated with proteinuria and foot process fusion, and mesangial cells demonstrate expansion with mesangial thickening. A low-protein diet slows the progression of disease parameters and has been attributed to a decrease in hyperfiltration load (56). Contrary to what one might expect from the effects of a low-protein diet, arginine supplementation resulted in higher GFR and renal plasma flow, and reduced glomerular and tubulointerstitial lesions in rats fed a normal diet (51). ODC mRNA and enzyme activity are shown to decrease in the remnant kidney from d 2 on, yet renal polyamine content is unchanged (52). Whether arginine supplementation increased polyamine levels after the initial insult, relative to uremic rats without arginine supplementation to aid in increasing compensatory growth of the remnant kidney, was not evaluated.

5.2. Hypertension

The kidneys play an important role in maintaining blood pressure. Renin produced by the kidneys will form angiotensin II (AII). AII is a vasoconstrictor molecule that also stimulates aldosterone secretion, which increases reabsorption of sodium and water. Increasing peripheral resistance and blood volume affects blood pressure. The kidney is important in maintaining sodium homeostasis. A fall in GFR will increase sodium reabsorption in an attempt to conserve sodium. Finally, the renal vasculature is maintained in a balance of vasoconstrictor (e.g., AII, endothelin) and vasodilator (e.g., NO, prostaglandins, platelet-activating factor) molecules. A shift in the equilibrium of any of these mechanisms can result in the pathogenesis of hypertension. It is not surprising then that hypertension accompanies chronic kidney disease.

Functional upregulation of AII mediates salt-sensitive hypertension in the Dahl salt-sensitive rat model (53). Increased AII can activate nicotinamide adenine dinu-cleotide/nicotinamide adenine dinucleotide phosphate oxidase, which produces superoxide anion (O2-). Interaction of O2- with NO produces peroxynitrite (OONO-), an RNOS. This could decrease bioactive NO for vasodilation, thus skewing the balance toward vasoconstriction and hypertension. On a high-salt diet, these rats exhibit increased blood pressure, a progressive decline in GFR, proteinuria, and glomerulosclerosis. Supplementation with arginine proved beneficial in alleviating hypertension and renal complications (54). In the Dahl salt-sensitive model, exogenous addition of spermidine attenuated the rise in blood pressure, whereas DFMO exaggerated the hypertension in high salt-treated, salt-sensitive rats (55). In that report, ODC protein expression in the proximal tubules increased, yet enzyme activity decreased in the hypertensive, saltsensitive animals. The effects of arginine supplementation on enzyme activity and polyamine production were not evaluated. A detailed description of polyamines and hypertension in the lung is presented in another chapter in this book (see Chapter 11).

5.3. Chronic Renal Failure

Patients with chronic renal failure display high polyamine levels. These levels are lowered significantly after dialysis (56,57). Polyamines are considered uremic toxins in renal failure patients. Only recently has this perception been properly investigated. In a careful study by Sakata et al. (58), analysis of the metabolic intermediates of polyamines revealed production of the oxidized product, acrolein, correlated with the degree of renal failure. Increased levels of polyamine oxidase in the blood of patients with chronic renal failure appeared responsible for the increased production of acrolein. Thus, therapeutic intervention with a polyamine oxidase inhibitor holds the hope of delaying disease progression of chronic renal failure and lowering mortality.

6. Acute Renal Failure

Acute renal failure (ARF) signifies rapid and severe suppression of renal function and urine flow. It is a common clinical condition associated with high morbidity and mortality. There are several conditions that can cause ARF, including urinary obstruction, organic vascular obstruction, massive infection, rapidly progressive glomeru-lonephritis, acute tubulointerstitial nephritis, disseminated intravascular renal coagulation, and acute tubular necrosis (ATN).

6.1. Acute Tubular Necrosis

The most common cause of ARF is ATN. Damage to the renal tubular epithelial cells in ATN results from ischemic or nephrotoxic causes. Tubular damage likely leads to the perturbation of several pathways. It can shift the balance of vasoconstrictors and vasodilators toward vasoconstriction. This is mediated in part by TGF and increased AII. Cast formation in ATN can lead to tubular blockage. In addition, excess back leak into the neighboring interstitium could eventually collapse the damaged tubule. Toxins can also cause lesions in the glomerular capillary wall and alter the ultrafiltration coefficient. All of these disturbances will decrease the GFR and result in oliguria. Progression is rapid and leads to high salt and water retention, azotemia, metabolic acidosis, and hyperkalemia; in other words, persistent renal failure. Fortunately, ATN is reversible. The tubule epithelial cells begin to repopulate at the onset of recovery, but the integrity of the tubules remain compromised so fluid and electrolyte loss occurs. Because of this loss, hypokalemia becomes a clinical issue. Prognosis of ATN depends on the cause, the stage of disease progression, the involvement of other organs, and appropriate management of blood electrolytes and water balance.

Arginine supplementation provides beneficial effects in the renal ischemia reperfusion injury (IRI) and nephrotoxic models of ARF, at least in part, the result of increases in NO generation (59). Until recently, little has been described about polyamine regulation in these renal models. Zahedi et al. (60) reported renal IRI significantly increased SSAT in renal tubules, with consequent increases in putrescine levels resulting from back conversion of polyamines. The authors went on to show that SSAT induction was specific to tubular injury as a's-platinum-mediated tubular injury increased SSAT protein expression, but uremia without tubular injury promoted by sodium depletion did not. An increase in back conversion of polyamines would generate H2O2 as a metabolic byproduct that could damage the tubules. This was observed in cultured kidney cells overexpressing SSAT (61). Furthermore, SSAT protein expression was upregulated by 2 h and was maintained over the 48-h experimental period. A characterized marker of renal cell injury, kidney injury molecule-1 (KIM-1), was transiently elevated by 12 h with maximal expression at 24 h after IRI. These data suggest SSAT may be an early marker of acute tubule injury and pathogenesis to ARF. Such a diagnostic marker could be decisive in early clinical detection and intervention.

7. Diabetes

Diabetes mellitus results in a multifactorial etiology. Type 1 diabetes affects the kidney in stages. At the very onset of diabetes, the kidney grows large and GFR becomes supranormal. Sclerosis and kidney failure occur many years later. The contemporary management of patients with diabetes is aimed toward slowing the progression to kidney failure after the onset of proteinuria and sclerosis. However, even the strictest regiment cannot entirely eradicate disease progression. The mechanisms responsible for the onset and progression of this disease have not been fully resolved.

7.1. Tubular Hypothesis

Many explanations have been offered for the elevated GFR and hyperfiltration in early diabetes. Most of these explanations are now cited in standard reference books and relate to signaling abnormalities within the glomerular microvessels (i.e., that the onset of renal diabetic complications are of glomerular origin). A recent approach argues that diabetic glomerular hyperfiltration is rooted, at least in part, in events that occur in the proximal tubule. There is now convincing evidence for a primary increase of fluid and electrolyte reabsorption in the proximal tubule in rats with streptozotocin (STZ)-induced experimental type 1 diabetes (62) and in early type 1 diabetes in humans (63). This rise in reabsorption is primary because it is not the consequence of glomerular hyperfiltration resulting from glomerulotubular balance. The increase in tubular transport in early diabetes mellitus is the combined result of an increased Na+/glucose cotransport, of tubular growth, and tubular dysfunction (62). Thus, aberrant reabsorption of salts from the proximal tubule results in lower salt concentrations reaching the macula densa. As mentioned, the macula densa is sensitive to salt load and feedback regulates GFR via TGF. Low salt arriving at the macula densa signals an increase in GFR. The spiraling increases in GFR to normalize the salt load at the macula densa lead to glomerular hyperfiltration and eventual glomerular damage (Fig. 3).

7.2. The Growth Response

It is postulated that the increase in size of the proximal tubule would cause an increase in salt reabsorption. But how much does growth alone contribute to the rise in GFR? Pharmacological inhibition of ODC with DFMO to reduce kidney growth directly correlates with reductions in proximal tubular hyperreabsorption in rats with early STZ diabetes (62). This illustrates the impact of tubular growth on kidney function in response to STZ. Before these experiments, proximal tubule hypertrophy was widely accepted to be a compensatory response to the load imposed by hyperfiltration. Understanding that diabetic proximal tubule growth is not just a response to hyperfiltration, but itself affects GFR, allows a better understanding of the mechanisms initiating the disease process and thus potential therapeutic intervention. Glomerular

Fig. 3. Proximal tubule-mediated glomerular hyperfiltration. (A) Diabetes increases salt reabsorption from the proximal tubule back to the blood. (B) This reduces the salt delivered to the macula densa, and (C) via tubuloglomerular feedback increases single nephron glomerular filtration rate. This cycle can result in hyperfiltration. G, glomerulus; GFR, glomerular filtration rate; PT, proximal tubule; MD, macula densa; TGF, tubuloglomerular feedback.

Fig. 3. Proximal tubule-mediated glomerular hyperfiltration. (A) Diabetes increases salt reabsorption from the proximal tubule back to the blood. (B) This reduces the salt delivered to the macula densa, and (C) via tubuloglomerular feedback increases single nephron glomerular filtration rate. This cycle can result in hyperfiltration. G, glomerulus; GFR, glomerular filtration rate; PT, proximal tubule; MD, macula densa; TGF, tubuloglomerular feedback.

expansion would also be affected by suppression of kidney growth. Whether proximal tubule transport is the primary mediator of glomerular hyperfiltration, or whether it is a contributing, yet essential, factor in the negative cycle of progressive dysfunction has yet to be resolved.

Pharmacological inhibition of ODC affects kidney growth and GFR, but is ODC activity pathophysiologically relevant in diabetes? Growth factors associated with the early onset of diabetes, including insulin-like growth factor (IGF-1), hepatocyte growth factor, platelet-derived growth factor, fibroblast growth factor, and synthetic diacyl-glycerol, all induce ODC activity. Induction of ODC activity can occur via the phospho-inositide 3-kinase (PI3K)/Akt (64) and protein kinase C pathways (65). Activation of the PI3K/Akt pathway brings about a complex and coordinated series of events with resultant antiapoptotic, pro-growth, survival, protein translation, cell-cycle entry, and angiogenic effects. IGF-1 may be the most studied mediator of the early growth phase in diabetes, and, as with vascular endothelial growth factor (VEGF), the effects of IGF-1 are attributed principally to the PI3K/Akt pathways. There are numerous examples of IGF-1 administration or overexpression increasing ODC activity, and ODC inhibition suppressing the mitogenic effects of IGF-1 (66). Furthermore, a functional mutation in the IGF-1 receptor prevents IGF-1 induction of ODC activity (67).

STZ-induced diabetes increases ODC activity several fold in the kidney, liver, and intestine, with maximum induction at 24 h. DFMO suppresses hypertrophy and hyper-plasia, and in jejunal mucosal enterocytes results in hypoplasia. The rapid yet transient induction of growth factors, such as IGF-1, temporally correlates with ODC expression and activity, induction of intracellular polyamines in the kidney cortex, and the prolifer-ative phase at the onset of STZ diabetes (62,68). ODC inhibition prevents the early increase in 5-bromodeoxyuridine-positive cells and blunts kidney growth, proximal tubular hyperreabsorption, and glomerular hyperfiltration in STZ diabetes (62).

Protein kinase C also gives rise to a set of complex effectors from mitotic to fibrotic, the latter primarily via transforming growth factor (TGF)-p. The diabetic kidney switches from hyperplastic to hypertrophic growth very early in the course of hyperglycemia (e.g., at around d 4 in the STZ model) (69), which matches the time frame of hyperplasia observed using 5-bromodeoxyuridine incorporation (68). TGF-P is an important mediator of this switch in diabetes, with receptor abundance decreasing during the early proliferative phase and increasing during the hypertrophic phase (69). TGF-P arrests cells in the Gj phase of the cell cycle by induction of the cyclin-dependent kinase inhibitor, p27KIP1. Thus kidney growth in the diabetic proximal tubule begins as a mitogen-induced growth response followed by cell-cycle arrest; that is, initial hyperplasia followed by hypertrophy. Renal hypertrophy continued in later stages of diabetes might be more a consequence of decreased proteolysis, thus increased intracellular protein buildup, than cell-cycle arrest (76).

If the early hyperplastic/hypertrophic growth is averted, will the later hypertrophy attributed to decreased proteolytic activity and other "downstream" diabetic complications be diminished as well? There is some evidence that it might (76). Wolf and Ziyadeh (71) note: "It is debatable whether or not these hypertrophic processes (in diabetes mellitus) will inevitably lead to irreversible fibrotic changes in humans, but experimental animal models provide ample evidence that this may indeed be the case." In these experimental animal models, growth always precedes glomerulosclerosis. Besides their involvement in the onset of diabetes, polyamines may be involved in the expansion of extracellular matrix and the progression of fibrosis in later stage diabetes as substrates for transglutaminase crosslinking (72). Polyamines and their regulation are emerging as important components in the onset and for the progression of renal complications from diabetes.

8. Conclusions

There are a large number of primary and secondary kidney diseases, and an equally large number of experimental models. Evaluations of the arginine/NOS/NO axis in these models are numerous and growing. Despite the relationship of the arginine/NO and arginine/polyamine pathways in inflammatory diseases, or their requirement in glomerulo or tubulo proliferative and hypertrophic growth, elucidation of polyamines and their regulation in the pathogenesis of renal disease is largely understudied. Considering the success of investigating the influence of polyamines in the examples given in this text, kidney disease appears fertile ground for future polyamine research.

Acknowledgments

I would like to thank my colleague, Dr. Volker Vallon, for his comments and contributions to this chapter. Supported in part by NIH grants DK070123, DK070667, DK02920, DK28602, DK056248; the American Cancer Society; UCSD Cancer Center; the Stein Institute for Research on Aging; and funds supplied by the Research Service of the Department of Veterans Affairs.

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