Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)–derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE–driven diabetes-mediated kidney injury.     

Impaired regulation of renal oxygen consumption in spontaneously hypertensive rats

Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 +/- 55 nmol O(2)/min per g, WKY: 611 +/- 51 nmol O(2)/min per g, P > 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin -13.9 +/- 1.9%, enalaprilat -15.3 +/- 1.6%, amlodipine -11.9 +/- 0.7%; WKY: bradykinin -22.8 +/- 1.0%, enalaprilat -24.1 +/- 2.0%, amlodipine -20.7 +/- 2.3%; P < 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempol. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation.     

Increased methylglyoxal and advanced glycation end products in kidney from spontaneously hypertensive rats

BACKGROUND: Methylglyoxal (MG), a metabolite of glucose, causes nonenzymatic glycation of proteins to form irreversible advanced glycation end products (AGEs). The role of MG in the development of essential hypertension is unknown, although MG has been extensively studied in relation to diabetes. METHODS: Blood pressure of spontaneously hypertensive rats (SHR) and paired Wistar Kyoto (WKY) rats was measured at 5, 8, 13, and 20 weeks of age. HPLC was used to determine the levels of plasma and kidney MG, as well as reduced or oxidized glutathione in the kidney. MG-induced AGEs, Nepsilon-carboxyethyl-lysine (CEL), and Nepsilon-carboxymethyl-lysine (CML) in the kidney were detected by immunohistochemistry. Glutathione peroxidase and reductase activities in the kidney were also determined. RESULTS: Plasma MG levels were significantly elevated in SHR, but not in WKY rats, at 8, 13, and 20 weeks of age in parallel with blood pressure increase. Kidney MG levels in SHR were increased by 21% and 38% at 13 and 20 weeks, respectively, compared to age-matched WKY rats. There were no differences in blood pressure and MG levels in plasma and kidney between SHR and WKY rats at 5 weeks of age. Immunohistochemistry revealed more intense staining for CML and CEL in kidneys from SHR compared to WKY rats from 8 weeks onward. Most of the staining was localized to renal tubules with some staining in the glomerular vessels. CONCLUSION: MG and AGEs formation was significantly elevated in kidney from SHR, which may cause local vascular and tubular damage, contributing to the development and complications of hypertension.     

20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease

Polycystic kidney diseases are characterized by abnormal proliferation of renal epithelial cells. In this study, the role of 20-hydroxyeicosatetraenoic acid (20-HETE), an endogenous cytochrome P450 metabolite of arachidonic acid with mitogenic properties, was evaluated in cystic renal disease. Daily administration of HET-0016, an inhibitor of 20-HETE synthesis, significantly reduced kidney size by half in the BPK mouse model of autosomal recessive polycystic kidney disease. In addition, compared with untreated BPK mice, this treatment significantly reduced collecting tubule cystic indices and approximately doubled survival. For evaluation of the role of 20-HETE as a mediator of epithelial cell proliferation, principal cells isolated from cystic BPK and noncystic Balb/c mice were genetically modified using lentiviral vectors. Noncystic Balb/c cells overproducing Cyp4a12 exhibited a four- to five-fold increase in cell proliferation compared with control Balb/c cells, and this increase was completely abolished when 20-HETE synthesis was inhibited; therefore, this study suggests that 20-HETE mediates proliferation of epithelial cells in the formation of renal cysts.     

Ultrastructural and functional abnormalities of intestinal and renal epithelium in the SHR

Intestinal calcium transport, renal tubular calcium reabsorption, and plasma 1.25 (OH)2 vitamin D3 (calcitriol) levels have all been reported to be diminished in the spontaneously hypertensive rat (SHR) compared with its genetic control the Wistar Kyoto rat (WKY). In the present study, absorptive duodenal and renal tubular epithelia of 12- to 14-week-old male SHR and WKY were examined by electron microscopy to determine whether such disturbances could be related to structural abnormalities. Patchy loss of microvilli in both duodenal and proximal tubular epithelia was observed in the SHR, whereas brush border membrane was entirely normal in the WKY. Irregular spaces were observed between the basal aspects of SHR intestinal epithelial cells and their basement membrane. In addition, the average height of duodenal and renal microvilli was reduced in the SHR. Two specific markers of the brush border membrane, alkaline phosphatase and villin, as well as the cytoplasmic vitamin-D dependent calcium-binding proteins, CaBP9K and CaBP28K were determined. Duodenal alkaline phosphatase activity was reduced in the SHR, compared with the WKY: 0.145 +/- 0.002 vs. 0.186 +/- 0.002 IE/min.microns 3 x 10(3) brush border, mean +/- SEM, N = 10 pairs, P less than 0.001. However, duodenal villin expression was not different from that of the WKY. Duodenal CaBP9K and renal CaBP28K content was diminished in the SHR: 21.0 +/- 0.80 vs. 29.9 +/- 2.19 micrograms/mg protein, N = 6 pairs, P less than 0.01 for duodenum, and 4.47 +/- 0.39 vs. 7.67 +/- 0.54 micrograms/mg protein, N = 6 pairs, P less than 0.001 for kidney. These data showing structural and functional abnormalities of intestinal and kidney cells in the SHR appear to reflect a disorder of transporting epithelia which may be either intrinsic or related to reduced circulating calcitriol.     

Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension

Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonist, increases renal tubular cytochrome P450 4a (Cyp4a) expression thereby increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. To determine if clofibrate affects blood pressure regulation we studied mice with DOCA-salt induced hypertension in wild-type and PPAR alpha knockout mice. Wild-type mice treated with DOCA-salt had higher mean arterial pressures and higher cumulative sodium balance, but lower renal 20-HETE production than did vehicle-treated mice. Treating DOCA-salt mice with clofibrate attenuated the increase in mean arterial pressure and cumulative sodium balance while increasing 20-HETE production and renal Cyp4a expression. In contrast the PPAR alpha knockout mice treated with clofibrate and DOCA-salt showed no attenuation in the increase of blood pressure, cumulative sodium balance, renal 20-HETE production or Cyp4a protein expression. Expression of the PPAR alpha protein was greater in proximal tubules than in renal microvessels. Our results show that PPAR alpha pathway induces renal tubular 20-HETE production which affects sodium retention and blood pressure regulation in DOCA-salt-treated mice.     

Cytochrome P450 metabolites of arachidonic acid in the control of renal function

Recent studies indicate that arachidonic acid is primarily metabolized by cytochrome P450 enzymes of the 4A and 2C families in the kidney to 20-hydroxyeicosatetraenoic acid (HETE), epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids. These compounds play central roles in the regulation of renal tubular and vascular function. 20-HETE is produced by renal vascular smooth muscle (VSM) cells and is a potent constrictor that depolarizes VSM cells by blocking the calcium-activated potassium channel. Inhibition of the formation of 20-HETE blocks the myogenic response of isolated renal arterioles in vitro, and autoregulation of renal blood flow and tubuloglomerular feedback responses in vivo. EETs are products formed in the endothelium and are potent dilators that activate the calcium-activated potassium channel in renal VSM. Endothelial-dependent vasodilators stimulate the release of EETs, and these compounds appear to serve as an endothelial-derived hyperpolarizing factor. EETs and 20-HETE are produced in the proximal tubule. There, they regulate sodium/potassium-ATPase activity and serve as second messengers for the natriuretic effects of dopamine, parathyroid hormone and angiotensin II. 20-HETE is also produced in the thick ascending loop of Henle. It regulates sodium-potassium-chloride transport in this nephron segment. The renal production of cytochrome P450 metabolites of arachidonic acid is altered in hypertension, diabetes, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of cytochrome P450 metabolites of arachidonic acid in the control of renal function, it is likely that changes in this system contribute to the abnormalities in renal function that are associated with many of these conditions.     

Responsiveness of cultured papillary collecting tubules to vasoactive hormones: comparison between spontaneously hypertensive rats and Wistar-Kyoto rats

To investigate whether altered renal medullary prostaglandin (PG) synthesis is involved in the development of hypertension in spontaneously hypertensive rats (SHR), we compared the hormonal responsiveness of cultured renal papillary collecting tubule (RPCT) cells from SHR and Wistar-Kyoto rats (WKY) as control. Basal levels of PGE2 and cAMP were lower in 4-weeks-old SHR than in WKY, while PGE2 synthesis after stimulation with arachidonate, A23187 or bradykinin and the level of cAMP responded to vasopressin or exogenous PGE2 were similar in both strains. There was no difference in basal nor stimulated levels of cGMP between both strains. In 16-week-old rats, basal levels of cAMP, cGMP and PGE2 were significantly lower than in 4-week-old rats, but no differences were recognized between both strains. These results suggest that RPCT cells of SHR and WKY at the post-weaning period may differ in the metabolism of PGE2 and cAMP. This difference may be attributed to the possible defect in arachidonate availability in SHR.     

Renal phosphate excretion in spontaneously hypertensive and normotensive Wistar Kyoto rats

Renal tubular reabsorption of phosphate was studied in unanesthetized spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY). Three-hour-urinary phosphate excretions of 12-week-old-male SHR (53.0 +/- 13.1 micrograms/mg creatinine, N = 7) and 14-week-old female SHR (81.8 +/- 12.8, N = 8) were significantly lower than those of age sex-matched WKY (12 week, 435.8 +/- 73.2, N = 8, P less than 0.01; 14 week, 423.3 +/- 75.9, N = 8, P less than 0.01). Renal clearances were performed in 14-week-old female rats after an overnight fast. The serum phosphate concentration of SHR (4.61 +/- 0.25 mg/dl) was lower than that of WKY (5.44 +/- 0.14, P less than 0.02). Urinary phosphate excretion (U Pi V = 6.85 +/- 1.83 micrograms/min) and fractional phosphate excretion (FE Pi = 13.7 +/- 2.3%) of SHR were lower than those of WKY (U Pi V = 15.9 +/- 1.87 micrograms/min, P less than 0.01, FE Pi 22.8 +/- 2.6%, P less than 0.02). Acute hyperventilation could not account for the lower excretion of phosphate in SHR, since arterial pH and PCO2 were not different between WKY and SHR. The low renal phosphate clearance of SHR was noted at a very early age; the U Pi V of 5-week-old SHR was already lower than that of WKY. Maximum tubular phosphate reabsorption (TmPi) was studied in the 12-week-old SHR and WKY after acute thyroparathyroidectomy. TmPi of SHR (241 +/- 3.0 micrograms/ml GFR/100 g, N = 7) was greater than that of WKY (204 +/- 7.0, N = 8, P less than 0.01). However, the differences in 3-hr urinary phosphate excretion and clearances of phosphate were abolished between SHR and WKY after their blood pressures were lowered by chronic hydralazine treatment. The results indicate that hypertension is responsible for the lower renal phosphate clearances in SHR.     

Interaction of endothelin with renal nerves modulates kidney function in spontaneously hypertensive rats

BACKGROUND AND METHODS: We investigated kidney function, renal endothelin-1 concentration, prepro-endothelin-1 mRNA as well as endothelin receptor A and B mRNA expression and receptor properties in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) with intact renal nerves and 7 days after renal denervation. In addition, responses of renal function to the non-selective ETA/ETB receptor blocker bosentan (10 mg/kg i.v. bolus injection) were studied. RESULTS: In SHR, renal papillary prepro-endothelin-1 mRNA expression, endothelin-1 tissue concentrations and endothelin receptor density were significantly lower than in normotensive rats. Renal denervation was associated with a decrease in papillary tissue prepro-endothelin-1 mRNA and in WKY rats also with a significant reduction in papillary endothelin-1 content without affecting ET receptor density. Bosentan did not alter renal blood flow or glomerular filtration rate but decreased urine flow rate in both intact normotensive and hypertensive rats, whereas it decreased urine sodium and potassium excretion only in intact WKY. Bosentan had no effects on renal function in renal denervated rats. CONCLUSION: Since renal papillary endothelin-1 appears to counteract the fluid and sodium retaining effects of renal nerve activity, an impaired renal endothelin-1 synthesis in SHR may contribute to excessive sodium retention and thus to the pathogenesis of hypertension in SHR.     

The effect of connective tissue growth factor on renal fibrosis and podocyte injury in hypertensive rats

Objective: The aim of this study was to evaluate the roles of podocalyxin (PCX) and connective tissue growth factor (CTGF) in spontaneously hypertensive rats. Methods: Spontaneously hypertensive rats (SHR) and normotensive control Wistar–Kyoto (WKY) rats were divided into groups referred to as SHR 12W, SHR 24W, WKY 12W and WKY 24W. Systolic blood pressure and 24-hour total uric protein were measured every two weeks in the respective groups. CTGF, PCX, alpha-smooth muscle actin (α-SMA) and collagen-III were evaluated via immunohistochemical staining. In addition, CTGF, PCX, and α-SMA gene expression levels were determined by analyzing mRNA levels. Results: More kidney lesions occurred alongside foot processes effacement in SHR 24W rats than in SHR 12W rats. In SHR 12W rats, blood pressure and 24-hour total uric protein level were elevated and continued to increase thereafter. In the SHR 12W and SHR 24W groups, the expression of CTGF, α-SMA and collagen-III was significantly increased. Immunohistochemical staining showed that PCX expression was significantly reduced in the SHR group and CTGF expression was increased. A significant decrease in PCX mRNA and an increase in CTGF mRNA were observed in SHR 24W rats relative to SHR 12W rats. Conclusion: Both the overexpression of CTGF and the loss of podocalyxin reflect renal damage in spontaneously hypertensive rats. CTGF and PCX may be involved in the mechanisms of podocyte injury and apoptosis induced by hypertension.     

Gender-related differences in advanced glycation endproducts, oxidative stress markers and nitric oxide synthases in rats

An age- and blood pressure-associated increase in methylglyoxal (MG) and MG-induced advanced glycation endproducts (AGEs), including N(epsilon)-carboxyethyl-lysine (CEL) and N(epsilon)-carboxymethyl-lysine (CML), in the kidney of spontaneously hypertensive rats (SHR) has been shown. In the present study, gender-related changes in AGEs and nitric oxide synthase were investigated in Sprague-Dawley (SD) and stroke-prone SHR (SHRsp) rats. Immunohistochemical analyses were conducted on kidneys from 24-week-old male and female SD rats as well as SHRsp. The systolic blood pressure of SHRsp was significantly higher than that of SD rats. Male SD rats had more intense kidney staining for CEL than female SD rats. Both male and female SHRsp had more marked CEL and CML staining localized to kidney tubules, as opposed to SD rats. Female rats showed more staining in glomerular vessels than male rats in both SD and SHRsp. Nuclei containing nuclear factor-kappaB (NF-kappaB) p65 and activated macrophages were seen in the kidney from SHRsp, not so much in SD rats, localized to renal tubules in male and glomerular vessels in female SHRsp. A higher protein level of NF-kappaB p65 was found in SHRsp than in SD rats. SD rats had more intense kidney neuronal nitric oxide synthase staining than SHRsp. The intensity of inducible nitric oxide synthase staining was significantly higher in SHRsp than in SD rats, with no gender differences in either strain. SHRsp and male rats exhibited higher AGEs and oxidative stress than SD and female rats, respectively. These differences might partly account for the development of hypertension in SHRsp and the higher vulnerability of male animals to renal pathology.     

足细胞分子nephrin在高血压大鼠肾脏的表达及作用

目的探讨足细胞分子nephrin在自发性高血压大鼠（SHR）肾脏的表达及作用。方法监测不同时期SHR与京都大鼠（wistar-kyotorats,WKY）尾动脉收缩压（SBP）、尿β2-微球蛋白（β2-MG）、尿素氮（BUN）、血肌酐（SCr）水平;免疫组化、RT-PCR方法检测nephrin蛋白及mRNA的表达,观察肾脏的病理改变。结果与WKY组相比,SHR组SBP、β2-MG、BUN、SCr升高,nephrin蛋白及mRNA表达量下降,且nephrin含量与尿β2-MG呈负相关。SHR组肾脏发生病理改变。结论足细胞分子nephrin在SHR肾小球表达减少,可能是导致足细胞裂隙膜损伤,引起尿β2-MG排泄水平增加,肾功能受损,肾脏病理改变的基础。     

Calcitriol synthesis is decreased in spontaneously hypertensive rats

To investigate the mechanisms of abnormal calcium metabolism, such as hypocalcemia, decreased intestinal calcium absorption and hypercalciuria in spontaneously hypertensive rats (SHR), we have measured the plasma concentration of calcitriol and its synthesis in 5-, 8-, 12-, 16-, and 20-week-old normotensive Wistar Kyoto rats (WKY) and SHR. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were measured by the constant isotope infusion method. Plasma concentration of calcitriol and PR of calcitriol were decreased in SHR after 12 weeks of age. MCR of calcitriol, however, was not different between WKY and SHR in any age group. Therefore, the decreased synthesis of calcitriol accounts for the lower plasma level of calcitriol in SHR after 12 weeks of age. Metabolic acidosis or decreased renal function could not account for the decreased synthesis of calcitriol, since the blood pH and pCO2 and creatinine clearance were similar between WKY and SHR at times when the calcitriol synthesis was reduced in SHR. Plasma concentration of ionized calcium was also lower in SHR after 12 weeks of age. Plasma concentration of calcitonin was significantly higher in 16-week-old SHR (41.6 +/- 1.5 pg/ml) than in age-matched WKY (30.5 +/- 1.7, P less than 0.001). The values, however, were not different between 8- and 12-week-old WKY and SHR. We believe that the decreased synthesis of calcitriol could be the pathogenetic factor for the development of abnormal calcium metabolism in SHR. Age of animals should be considered when studying the calcium metabolism in SHR.     

高盐饮食对自发性高血压大鼠肾髓质环氧化酶2表达的影响

目的观察自发性高血压大鼠（SHR）肾髓质环氧化酶2（COX2）的表达以及不同盐负荷状态下COX2的变化。方法6周龄SHR大鼠及其对照Wistar-Kyoto（WKY）大鼠各12只，随机分为低盐组和高盐组（WKY-LS组，WKY-HS组，SHR-LS组，SHR-HS组），分别给予高盐（含8％NaCl）或低盐（含O．04％NaCl）饮食3d。观察基础状态及不同盐负荷前后大鼠尾动脉血压、24h尿量（UV）、尿钠（UNa）以及COX2代谢物6k．PGFlα排泄情况。应用免疫组化和Western印迹的方法检测肾髓质COX2蛋白表达。结果给予不同盐负荷3d后，SHR-Hs组血压显著升高[（12．59±5．13）比（11．94±3．76）mmHg，P〈0．05]。基础状态及不同盐负荷状态下，SHR大鼠24hUV、UNa排泄与WKY大鼠相比均显著下降（P均〈O．05）。与各自基础状态相比，低盐饮食后两种大鼠的UV和UNa排泄显著降低；高盐饮食后则显著增加（P均〈O．05）。SHR和WKY大鼠尿COX2代谢物6k-PGFlα的排泄对盐负荷的反应也类似，高盐组均较低盐组显著增加（P〈0．05），但同样盐负荷状态下两组之间差异无统计学意义。基础状态下及低盐饮食SHR与WKY大鼠肾髓质COX2表达差异无统计学意义；给予高盐饮食后WKY大鼠肾髓质COX2表达增加2．06倍，SHR大鼠增加1．87倍，但两种大鼠之间差异无统计学意义。结论SHR大鼠肾脏水盐排泄功能受损，高盐饮食后血压进一步升高，水钠潴留，同时伴有肾髓质COX2表达升高，但不同盐负荷对SHR大鼠肾髓质COX2表达的影响与WKY大鼠相同。提示肾髓质COX2参与了水盐代谢的调节，且在SHR大鼠中表达正常，但并非该动物模型高血压形成及水钠潴留的关键因素。     

Modulation of vascular function by neuropeptide Y during development of hypertension in spontaneously hypertensive rats

Neuropeptide Y (NPY) is a sympathetic cotransmitter and a platelet-derived factor which causes vasoconstriction, potentiation of norepinephrine (NE) action, and vascular mitogenic effects. Reciprocally, NE markedly enhances the actions of NPY. We studied vasopressor effects of NPY and sources of peptide release during the development of hypertension in spontaneously hypertensive rats (SHR). Conscious SHR (4 and 16 weeks old) had higher resting plasma levels of NE and epinephrine than age-matched Wistar-Kyoto (WKY) rats, but similar NPY immunoreactivity (NPY-ir) levels in platelet-poor plasmas (PPP). In both strains, NPY-ir levels in PPP were higher in 4-week-old than in older rats. However, at all ages (4–24 weeks) SHR had markedly elevated NPY-ir content in platelet-rich-plasmas than WKY rats, although levels declined with age and hypertension. In the superior mesenteric artery. NPY-ir content (per mg) was significantly higher in 4-week-old but lower in 16-week-old SHR than in WKY rats, suggesting greater sympatho-neural NPY stores and release (leading to depletion) during the development of hypertension. Four-week-old SHR also tended to have higher NPY-ir content in the adrenal medullae and coeliac ganglia but a lower content in the kidney than WKY rats; these differences disappeared with age. Pressor responsiveness to -agonists and NPY were similar in both strains at 4 weeks. While unchanged by age in WKY rats, adrenergic and NPY-mediated vasopressor responses became augmented in 16- to 24-week-old SHR (compared with WKY rats); this hyperresponsiveness was not completely abolished by ganglionic blockade and not observed with vasopressin. The development of adrenergic hyperresponsiveness in SHR in the face of higher circulating catecholamines suggests a defect in downregulation of -adrenoceptors. Since we have previously found that NPY can reverse pressor desensitization to NE, we postulate that increased release of platelet and sympatho-neural NPY leads to impaired adrenergic desensitization, whereas adrenergic/NPY interactions tesult in sensitization to NPY in SHR, and thus may contribute to vascular hyperreactivity and hypertrophy.     

Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury

20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20-hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies.     

Renal oxygenation defects in the spontaneously hypertensive rat: role of AT1 receptors

BACKGROUND: The spontaneously hypertensive rat (SHR) has oxidative stress and enhanced O2 usage (Q(O2)) relative to tubular sodium transport (TNa). Angiotensin II (Ang II) acting on Type I receptors (AT1-R) causes renal oxidative stress and functional nitric oxide (NO) deficiency that could enhance O2 usage. Therefore, we investigated the hypothesis that AT1-Rs mediate the inefficient renal oxygenation in the SHR. METHODS: Groups of SHR and WKY received vehicle (Veh), candesartan (Cand) or hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. RESULTS: Compared to WKY + Veh, the elevated BP of SHR + Veh (153 +/- 3 vs 115 +/- 3 mm Hg; P < 0.001) was normalized by Cand (117 +/- 4) or HHR (113 +/- 5 mm Hg). The reduced renal blood flow of SHR + Veh (2.4 +/- 0.3 vs. 4.1 +/- 0.3 mL. min-1. 100 g-1) was increased (P < 0.05) by Cand (3.6 +/- 0.3) and HHR (3.2 +/- 0.2). Compared to WKY + Veh, SHR + Veh had a 50% reduction in TNa: (16.9 +/- 2.0 vs. 7.8 +/- 0.9 micromol: micromol-1, P < 0.01) that was unchanged by HHR (8.6 +/- 1.1), but was increased by Cand (13.2 +/- 1.4; P < 0.01). The pO2 of outer cortex was lower in SHR + Veh than WKY + Veh (31 +/- 3 vs. 41 +/- 2 mm Hg; P < 0.05) and it was not changed significantly by HHR (37 +/- 2) but was normalized by Cand (44 +/- 3 mm Hg; P < 0.01). The pO2 in the deep cortex also was lower in SHR + Veh than WKY + Veh (18 +/- 3 vs. 30 +/- 3 mm Hg; P < 0.005) and was not changed significantly by HHR (19 +/- 2), but was increased by Cand (25 +/- 3 mm Hg; P < 0.05). CONCLUSIONS: The reduced pO2 in outer and inner cortex, and inefficient utilization of O2 for Na+ transport in the SHR kidney can be ascribed to the effects of AT1-R, largely independent of blood pressure.     

Role of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in hypertension

PURPOSE OF REVIEW: Cytochrome P-450 metabolites of arachidonic acid have been reported to play an important role in the control of renal function and vascular tone, and in the long-term control of arterial pressure. In this regard, 20-hydroxyeicosatetraenoic acid is a potent vasoconstrictor that inhibits sodium reabsorption in the kidney. Epoxyeicosatrienoic acids are endothelium-derived relaxing factors that hyperpolarize vascular smooth muscle cells and also promote sodium excretion in the kidney. RECENT FINDINGS: Studies have demonstrated that the expression of cytochrome P-450 enzymes and the synthesis of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in the kidney and peripheral vasculature are altered in many genetic and experimental models of hypertension. The production of these compounds is altered following exposure to high-salt or high-fat diets, in hepatorenal syndrome, in diabetes and in patients with toxemia of pregnancy. However, the functional significance of changes in the formation of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in the pathogenesis of hypertension are just being uncovered. SUMMARY: This review summarizes recent findings that address the issue of whether cytochrome P-450 metabolites of arachidonic acid play an important role in the regulation of renal tubular and peripheral vascular function and contribute to the pathogenesis of hypertension.