As covered in the preceding sections, acute renal failure (ARF) is a syndrome associated with high mortality in humans. Current therapy is limited to supportive measures and preventive strategies, none of which have been definitively shown to alter mortality. Ischemic ARF is often associated with

Recent Advances in the Pathophysiology of Ischemic Acute Renal Failure

Nuclear receptors (NRs) are ligand-dependent transcription factors whose activation affects genes controlling vital processes. Among them, the peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity. PPARs are activated by fatty acids and their derivatives, many of which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus. Tissues that play a role in whole-body metabolic homeostasis, such as adipose tissue, liver, skeletal muscle, intestines, and blood vessel walls, are prone to inflammation when metabolism is disturbed, a complication that promotes type 2 diabetes and cardiovascular disease. This review discusses the protective roles of PPARs in inflammatory conditions and the therapeutic anti-inflammatory potential of PPAR ligands.

https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(12)00070-7.pdf

PPARs at the crossroads of lipid signaling and inflammation

Oxidative stress and vascular inflammation in aging

Objective:The aim was to clarify how smoking and nicotine affects wound healing processes and to establish if smoking cessation and nicotine replacement therapy reverse the mechanisms involved.Background:Smoking is a recognized risk factor for healing complications after surgery, but the pathophysio

Wound healing and infection in surgery: the pathophysiological impact of smoking, smoking cessation, and nicotine replacement therapy: a systematic review.

Advancing age promotes cardiovascular disease (CVD), the leading cause of death in the United States and many developed nations Two major age-related arterial phenotypes, large elastic artery stif

Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease

Nitric oxide (NO) regulates renal proximal tubular (PT) Na+ handling through modulation of Na+-K+ ATPase. Peroxisome Proliferator Activated Receptorα (PPARα), a nuclear transcription factor, is expressed in PTs and has been reported to influence NO generation/activity in renal tissues. This study tested the hypothesis that PPARα interacts with NO and thereby affects renal tubular Na+ transport. Urinary excretion of nitrite (UNOXV) and Na+ (UNaV) and PT Na+ transport (Na+-K+ ATPase activity) were determined in rats treated with clofibrate (250 mg/kg i.p) or WY14643 (45 mg/kg; i.p.), a PPARα ligand, 2% NaCl (orally), clofibrate/NaCl, L-NAME, an inhibitor of NO production (100 mg/kg; orally), L-NAME/Clofibrate. Clofibrate or WY14643 increased PPARα expression by 106 ± 7% (p < 0.05) and 113 ± 8% (p < 0.05), respectively. Similarly, clofibrate and WY14643 increased expression of MCAD, a downstream target protein of PPARα by 123 ± 8% (p < 0.05) and 143 ± 8% (p < 0.05), respectively. L-NAME attenuated clofibrate-induced increase in PPARα expression by 27 ± 2% (p < 0.05) but did not affect MCAD expression. UNOXV excretion increased 3–4 fold in rats treated with clofibrate, WY14643 or NaCl from 44 ± 7 to 170 ± 15, 144 ± 18 or 132 ± 11 nmol/24 hr, respectively (p < 0.05). Similarly, clofibrate, WY14643 or NaCl elicited a 2–5 fold increase in UNaV. L-NAME significantly reduced basal UNOXV and UNaV and abolished the clofibrate-induced increase. Clofibrate, WY14643, NaCl or clofibrate + NaCl treatment reduced Na+-K+-ATPase activity in the PT by 89 ± 23, 62 ± 10, 43 ± 9 and 82 ± 15% (p < 0.05), respectively. On the contrary, L-NAME or ODQ, inhibitor of sGC, abolished the inhibition of Na+-K+-ATPase activity by clofibrate (p < 0.05). Clofibrate either alone or with NaCl elicited ~2-fold increase in the expression of the α1 subunit of Na+-K+ ATPase in the PT while L-NAME abolished clofibrate-induced increase in Na+-K+ ATPase expression. These data suggest that PPARα activation, through increased NO generation promotes renal excretion of Na+ through reduced Na+-K+ ATPase activity in the PT probably via post translational modification of Na+-K+-ATPase.

/pdf/relationship-between-ppara-activation-and-no-on-proximal-1t19w84h9p.pdf

Relationship between PPARα activation and NO on proximal tubular Na+ transport in the rat

Loss of nitric oxide and endothelial-derived hyperpolarizing factor-mediated responses in aging

Acrolein, an environmental pollutant and a lipid peroxidation product, is implicated in vascular pathogenesis. Although evidence indicates a link between vascular pathogenesis and acrolein, no direct studies relating to effects of acrolein on vascular function and responses are known. This study investigated the effects of acrolein on vascular function to understand the underlying mechanism of acrolein-induced vascular responses. Male Sprague-Dawley rats were treated with acrolein (2 or 4 mg/kg; i.p.) for 3 or 7 days. Urine and blood samples were collected. Changes in systolic blood pressure (SBP) and responses to acetylcholine and phenylephrine were determined. Acrolein (4 mg/kg, 7 days) significantly increased SBP by 25%, phenylephrine vasoconstriction by 2-fold, but decreased urinary excretion of nitrite by 25%. Acrolein inhibited generation of cyclic guanosine 3'5'-monophosphate (cGMP) by 98%, and did not alter expression of nitric oxide synthase (eNOS). Acrolein increased the generation of lipid hydroperoxide in plasma and aortic tissue by 21% and 124% respectively, increased glutathione-S-transferase (GST) and glutathione peroxidase (GSH-Px) activities. Acrolein up-regulated the expression of GST by 2 fold. These data suggest that induced SBP and altered vasoconstriction/vasodilatation in acrolein treated rats may be due to reduced availability of NO via increased free radical generation and reduced antioxidant defense.

/pdf/mechanism-of-acrolein-induced-vascular-toxicity-kfercrf0ro.pdf

Mechanism of acrolein-induced vascular toxicity.

Activation of peroxisome proliferator activated receptor (PPAR)alpha and its protective role in cardiovascular function has been reported but the exact mechanism(s) involved is not clear. As we have shown that PPARalpha ligands increased nitric oxide (NO) production and cardiovascular function is controlled by a balance between NO and free radicals, we hypothesize that PPARalpha activation tilts the balance between NO and free radicals and that this mechanism defines the protective effects of PPARalpha ligands on cardiovascular system. Systolic blood pressure (SBP) was greater in PPARalpha knockout (KO) mice compared with its wild type (WT) litter mates (130+/-10 mmHg versus 107+/-4 mmHg). L-NAME (100mg/L p.o.), the inhibitor of NO production abolished the difference between PPARalpha KO and WT mice. In kidney homogenates, tissue lipid hydroperoxide generation was greater in KO mice (11.8+/-1.4 pM/mg versus 8.3+/-0.6 pM/mg protein). This was accompanied by a higher total NOS activity (46+/-6%, p<0.05) and a approximately 3 fold greater Ca2+-dependent NOS activity in kidney homogenates of untreated PPARalpha WT compared with the KO mice. Clofibrate, a PPARalpha ligand, increased NOS activity in WT but not KO mice. Bezafibrate (30 mg/kg) reduced SBP in conscious rats (19+/-4%, p<0.05), increased urinary NO excretion (4.06+/-0.53-7.07+/-1.59 microM/24 h; p<0.05) and reduced plasma 8-isoprostane level (45.8+/-15 microM versus 31.4+/-8 microM), and NADP(H) oxidase activity (16+/-5%). Implantation of DOCA pellet (20mg s.c.) in uninephrectomized mice placed on 1% NaCl drinking water increased SBP by a margin that was markedly greater in KO mice (193+/-13 mmHg versus 130+/-12 mmHg). In the rat, DOCA increased SBP and NAD(P)H oxidase activity and both effects were diminished by clofibrate. In addition, clofibrate reduced ET-1 production in DOCA/salt hypertensive rats. Thus, apart from inhibition of ET-1 production, PPARalpha activation exerts protective actions in hypertension via a mechanism that involves NO production and/or inhibition of NAD(P)H oxidase activity.

NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)alpha-mediated cardiovascular effects.

End organ damage in essential hypertension has been linked to increased oxygen free radical generation, reduced antioxidant defense, and/or attenuation of nitric oxide synthase (NOS) activity. Ascorbic acid (AA), a water-soluble antioxidant, has been reported as a strong defense against free radicals in both aqueous and nonaqueous environment. In this study we examined the hypothesis that antioxidant ascorbic acid may confer protection from increased free radical activity in brain, liver, and blood vessels of spontaneously hypertensive rats (SHR). Male SHRs were divided into groups: SHR + AA (treated with AA, 1 mg/rat/day; for 12 weeks) or SHR (untreated). Wister-Kyoto rats (WKY) served as the control. Mean systolic blood pressure (SBP) in treated and untreated SHR was 145 +/- 7 mmHg and 142 +/- 8 mmHg, respectively. AA treatment prevented the increase in systolic blood pressure in SHR by 37 +/- 1% (p < 0.05). NOS activity in the brain, liver, and blood vessels of WKY rat was 1.82 +/- 0.02, 0.14 +/- 0.003, and 1.54 +/- 0.06 pmol citruline/mg protein, respectively. In SHR, total NOS activity was significantly reduced by 52 +/- 1%, 21 +/- 3%, and 44 +/- 4%, respectively. AA increased NOS activity in brain, liver, and blood vessels of SHR from 0.87 +/-.03, 0.11 +/-.01, and 0.87 +/-.08 pmol citruline/mg protein to 0.93 +/- 0.01, 0.13 +/- 0.001, and 1.11 +/- 0.03 pmol citruline/mg protein (p < 0.05), respectively. Lipid peroxides in the brain, liver, and blood vessels from WKY rats were 0.87 +/- 0.06, 0.11 +/- 0.005, and 0.47 +/- 0.04 nmol MDA equiv/mg protein, respectively. In SHR, lipid peroxides in brain, liver, and blood vessels were significantly increased by 40 +/- 3%, 64 +/- 3%, and 104 +/- 13%, respectively. AA reduced lipid peroxidation in liver and blood vessels by 17 +/- 1% and 34 +/- 3% but not in brain. Plasma lipid peroxides were almost doubled in SHR (p < 0.01) together with a reduction in total antioxidant status (6 +/- 0.1%; p < 0.05), nitrite (53 +/- 2%; p < 0.05) and superoxide dismutase (SOD) activity (36 +/- 2%; p < 0.05). AA treatment reduced plasma lipid peroxide (p < 0.001), and increased TAS (p < 0.001), nitrite (p < 0.001), and SOD activity (p < 0.001). From this study, we conclude that brain, liver, and blood vessels in SHR are susceptible to free radical injury, which reduces the availability of NO either by scavenging it or by reducing its production via inhibiting NOS. In addition, brain, liver, and blood vessels in SHR; may be protected by antioxidant, which improves total antioxidant status, and SOD thus may prevent high blood pressure and its complications.

Modulation of nitric oxide synthase activity in brain, liver, and blood vessels of spontaneously hypertensive rats by ascorbic acid: protection from free radical injury.

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