. Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291: F1090 -F1095, 2006; doi:10.1152/ajprenal.00517.2005.-Acute renal failure (ARF) in septic patients drastically increases the mortality to 50 -80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-␣ (TNF-␣), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-␣ and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-␣ and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 Ϯ 6.6 vs. 50.2 Ϯ 6.6 l/min, P Ͻ 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-␣ (1.00 Ϯ 0.55 vs. 7.02 Ϯ 2.40 pg/ml, P Ͻ 0.05) and serum IL-1␤ (31.3 Ϯ 3.6 vs. 53.3 Ϯ 5.9 pg/ml, P Ͻ 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 Ϯ 18.0 vs. 44.5 Ϯ 16.2 l/min, P Ͻ 0.05) and renal blood flow (0.86 Ϯ 0.08 vs. 0.59 Ϯ 0.05 ml/min, P Ͻ 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 Ϯ 5.8 vs. 178.0 Ϯ 7.6 mmHg ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-␣, IL-1␤, and NO as well as a decrease in renal iNOS and ICAM-1. sepsis; tumor necrosis factor SEPSIS IS KNOWN TO OCCUR annually in 751,000 Americans and accounts for 215,000 deaths, a number equivalent to the overall deaths due to myocardial infarction (1). Moreover, sepsis is a major cause of acute renal failure (ARF) in intensive care units; sepsis-related ARF is associated with a 70 -80% mortality (33,34).Both inflammatory and vasoactive mediators are involved in the pathophysiology of sepsis-related ARF. TNF-␣ plays a central role in this process. Serum levels of TNF-␣ are induced early in endotoxemia in humans (25). Moreover, elevated serum levels of the type I and type II receptors for TNF-␣ are shown to be predictive factors for ARF in patients with septic shock (12). The role of TNF-␣ as a pathogenetic factor in experimental ARF was supported by the observation that pretreatment with a TNF-soluble receptor (TNF s R p55 ) significantly attenuated endotoxemia-related ARF (19). It has also been shown that endotoxemic ARF is caused by TNF acting directly on TNF receptor-1 in the kidney (6). TNF-␣ participates in the magnification of the response mediated by the release of other cytokines and active substan...

This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction.

toxin-related acute kidney injury has been shown to profoundly induce nitric oxide (NO), which activates sympathetic and reninangiotensin system, resulting in renal vasoconstriction. While vascular muscle cells are known to upregulate inducible NO synthase (iNOS), less is known about the endothelium as a source of NO during endotoxemia. Studies were, therefore, undertaken both in vitro in mouse microvascular endothelial cells and in vivo in transgenic mice with overexpression of endothelial GTP cyclohydrolase, the ratelimiting enzyme for tetrahydrobiopterin, a cofactor for NO synthase. LPS significantly induced endothelial cell iNOS expression and NO concentration in the culture media, with no change in endothelial NO synthase expression. GTP cyclohydrolase-1 transgenic (Tg) mice demonstrated a significant increase in baseline urine NO-to-creatinine ratio and a more significant increase in renal iNOS expression and serum NO levels with LPS treatment compared with the wild-type (WT) mice. Glomerular filtration rate and renal blood flow decreased significantly in Tg mice with 1.0 mg/kg LPS, while no changes were observed in WT with the same dose of LPS. Serum IL-6 levels were significantly higher in Tg compared with WT mice during endotoxemia. The antioxidant tempol improved the glomerular filtration rate in the Tg mice. Thus endothelium can be an important source of iNOS and serum NO concentration during endotoxemia, thereby increasing the sensitivity to AKI. Reactive oxygen species appear to be involved in this acute renal injury in Tg mice during endotoxemia. nitric oxide; nitric oxide synthase; IL-6; reactive oxygen species THE ANNUAL DEATHS IN THE UNITED States related to sepsis are estimated to be 210,000, a number in excess of deaths due to acute myocardial infarction (2). The mortality with sepsis is strikingly increased when associated with acute kidney injury (AKI). In contrast to the approximate 45% mortality of AKI in nonseptic patients, the association of sepsis and AKI has a 70% mortality (8,15).Bacterial endotoxin accounts for much of the hemodynamic, hormonal, and inflammatory responses to gram-negative sepsis (14); therefore, the effects of endotoxemia with lipopolysaccharide (LPS) on renal function have been examined in various species. In recent years, endotoxemia-related AKI in mice has been investigated because of the molecular advantages of transgenic and knockout mice.Endotoxin-related AKI has been shown to profoundly induce nitric oxide (NO) (10, 11). The resultant increase in systemic and renal NO has potential deleterious effects, including systemic vasodilation with activation of the sympathetic and renin-angiotensin system and resultant renal vasoconstriction (17), as well as combining with oxygen radicals to produce the injurious peroxynitrite compound (18). While vascular smooth muscle cells are known to upregulate inducible NO synthase (NOS) (iNOS) in response to endotoxin and cytokines (3, 5), less is known about the endothelium as a source of NO during endotoxemia.Studies were, the...

Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin (PGI(2)), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant) as urinary excretion of 6-keto-PGF(1alpha), the major metabolite of PGI(2), increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF(1alpha), the same low dose of LPS significantly decreased GFR (110.7 +/- 12.1 vs. 173.3 +/- 6.7 microl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI(2) in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF(1alpha). These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 +/- 3.9 vs. 196.5 +/- 21.0 microl/min P < 0.01), which did not alter GFR in WT mice (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI(2)-cAMP-renin system in these Tg mice. Moreover, angiotensin-converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus endothelial PGIs-mediated PGI(2), as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal-specific PGIs Tg mice.

The pathogenesis of septic acute renal failure (ARF) involves systemic vasodilation with compensatory upregulation of vasoconstrictors. This can lead to renal vasoconstriction and ARF. Heme oxygenase (HO) is the rate-limiting step in heme metabolism and produces carbon monoxide (CO) and biliverdin. HO-1 is an inducible form of the enzyme and is expressed in response to cell injury. It was hypothesized in endotoxemia, induction of HO-1 would lead to increased production of the vasodilator CO, lower blood pressure, and decrease renal function. The role of HO-1 was therefore examined in a mouse model of endotoxemia. One group of mice received LPS alone and were compared with mice that received LPS in addition to an inhibitor of HO-1, zinc protoporphyrin (ZnPP). Treatment of mice with LPS resulted in significant increases in the protein expression of HO-1 compared with controls treated with vehicle. Immunohistochemical analysis localized this upregulation to both the proximal and distal tubules as well as the vasculature. Hemodynamic studies were performed during endotoxemia and the mean arterial pressure (MAP) was found to be significantly higher in the HO-1 inhibitor-treated compared with vehicle-treated mice (78 +/- 3 vs. 64 +/- 2 mmHg, P < 0.01). It was found that the inhibitor group had higher renal blood flows (RBF) also during endotoxemia (1.8 +/- 0.2 vs. 0.68 +/- 0.1 ml/min, P < 0.01). Furthermore, when renal vascular resistance (RVR) was calculated, there was a significant decrease in RVR in the inhibitor group (43.5 +/- 3.4 vs. 95.9 +/- 11.3 mmHg.ml(-1).min(-1), P < 0.01). In concert with the hemodynamic data, glomerular filtration rate (GFR), as measured by inulin clearance, was higher in the HO inhibitor compared with the vehicle controls during endotoxemia (111.5 +/- 19.5 vs. 66.0 +/- 3.5 microl/min, P < 0.05). In summary, during endotoxemia ARF, inhibiting HO-1 with ZnPP resulted in the protection of renal function. The renal protection was associated with significantly improved systemic hemodynamics, less renal vasoconstriction, and a higher GFR.