SUMMARY The prevalence of diabetes has dramatically increased worldwide due to the vast increase in the obesity rate. Diabetic nephropathy is one of the major complications of type 1 and type 2 diabetes and it is currently the leading cause of end‐stage renal disease. Hyperglycemia is the driving force for the development of diabetic nephropathy. It is well known that hyperglycemia increases the production of free radicals resulting in oxidative stress. While increases in oxidative stress have been shown to contribute to the development and progression of diabetic nephropathy, the mechanisms by which this occurs are still being investigated. Historically, diabetes was not thought to be an immune disease; however, there is increasing evidence supporting a role for inflammation in type 1 and type 2 diabetes. Inflammatory cells, cytokines, and profibrotic growth factors including transforming growth factor‐β (TGF‐β), monocyte chemoattractant protein‐1 (MCP‐1), connective tissue growth factor (CTGF), tumor necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), interleukin‐18 (IL‐18), and cell adhesion molecules (CAMs) have all been implicated in the pathogenesis of diabetic nephropathy via increased vascular inflammation and fibrosis. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species are a primary candidate. Thus, targeting oxidative stress‐inflammatory cytokine signaling could improve therapeutic options for diabetic nephropathy. The current review will focus on understanding the relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy to help elucidate the question of which comes first in the progression of diabetic nephropathy, oxidative stress, or inflammation.

Females are less sensitive to the hypertensive effects of angiotensin II compared to males, although the molecular mechanisms responsible are unknown. We hypothesize that differential activation of angiotensin II, Ang (1–7), AT1, AT2, and mas levels in the renal cortex of male and female spontaneously hypertensive rats contribute to sex differences in the blood pressure response to angiotensin II infusion. Males had a greater increase in blood pressure following angiotensin II infusion than females (males: 150±2 to 186±3 mmHg; females: 137±3 to 160±4 mmHg; p<0.05). Angiotensin II infusion resulted in comparable increases in plasma and renal cortical angiotensin II levels in both sexes. Renal cortical Ang (1–7) levels were higher in female rats under basal conditions (195±10 vs. 67±11 ng/gram cortex, p<0.05) and following angiotensin II infusion (281±25 vs. 205±47 ng/gram cortex, p<0.05) compared to male rats. In the renal cortex of male rats, angiotensin II infusion decreased AT1 protein expression and increased AT2 expression with no change in mas expression. In female rats there was an increase in mas receptor protein expression with angiotensin II infusion although AT1 and AT2 expression were unchanged. Male and female rats were then treated with the Ang (1–7) mas receptor antagonist, A-779, in the absence and presence of angiotensin II. A-779 equalized the blood pressure response to angiotensin II in males and females (blood pressure at the end of treatment: males, 166±4; females, 164±5 mmHg). In conclusion, Ang (1–7) contributes to the sex difference in angiotensin II-induced increases in blood pressure in spontaneously hypertensive rats.

Studies suggest that the inflammatory cytokine TNF-alpha plays a role in the prognosis of end-stage renal diseases. We previously showed that TNF-alpha inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-alpha contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n = 5 or 6) were studied for 3 wk with the following treatments: 1) placebo, 2) placebo + TNF-alpha inhibitor etanercept (1.25 mg.kg(-1).day(-1) sc), 3) deoxycorticosterone acetate + 0.9% NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared with baseline (177 +/- 4 vs. 107 +/- 3 mmHg; P < 0.05), and TNF-alpha inhibition had no effect in the elevation of MAP in these rats (177 +/- 8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared with placebo (703 +/- 76 vs. 198 +/- 5 mg/day); etanercept lowered the proteinuria (514 +/- 64 mg/day; P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary monocyte chemoattractant protein (MCP)-1 and endothelin (ET)-1 excretion were also increased in DOCA-salt rats compared with placebo (MCP-1: 939 +/- 104 vs. 43 +/- 7 ng/day, ET-1: 3.30 +/- 0.29 vs. 1.07 +/- 0.03 fmol/day; both P < 0.05); TNF-alpha inhibition significantly decreased both MCP-1 and ET-1 excretion (409 +/- 138 ng/day and 2.42 +/- 0.22 fmol/day, respectively; both P < 0.05 vs. DOCA-salt alone). Renal cortical NF-kappaB activity also increased in DOCA-salt hypertensive rats, and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-alpha contributes to the increase in renal inflammation in DOCA-salt rats.

Abstract-We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) ␣ contributes to hypertension and renal injury in salt-sensitive angiotensin hypertension. Male Sprague-Dawley rats were fed a high-salt diet (8% NaCl), and osmotic minipumps were implanted to deliver angiotensin II for 14 days. Rats were divided into 3 groups: high salt, angiotensin high salt, and angiotensin high salt administered the TNF-␣ blocker, etanercept. Arterial pressure increased from 94Ϯ5 to 148Ϯ7 mm Hg during week 1 in the angiotensin high-salt group, whereas etanercept slowed blood pressure elevation during the first week in the treated group (90Ϯ2 to 109Ϯ6 mm Hg). After 2 weeks, arterial pressure increased to 156Ϯ11 mm Hg in the angiotensin high-salt group and 141Ϯ6 mm Hg in the etanercept-treated group. Albuminuria and proteinuria were significantly elevated in angiotensin high-salt rats and were reduced in the etanercept-treated rats. Urinary monocyte chemoattractant protein-1 excretion significantly increased in the angiotensin high-salt group (275Ϯ47 versus 81Ϯ19 ng/day) and was decreased in the etanercept-treated group (153Ϯ31 ng/day). Angiotensin high-salt rats also had a significant increase in renal monocyte/macrophage infiltration, and this was again attenuated by etanercept treatment. Renal expression of Cyp2c23 decreased, whereas renal epoxide hydrolase expression increased in angiotensin high-salt rats. Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression. These data suggest that TNF-␣ contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension. Key Words: sodium, dietary Ⅲ angiotensin Ⅲ tumor necrosis factor Ⅲ blood pressure Ⅲ proteinuria Ⅲ metabolism P revious studies have shown that the renin-angiotensin system is important in the regulation of blood pressure, aldosterone release, and sodium reabsorption. 1 Angiotensin II (Ang II) is a potent proinflammatory agent and mediates inflammatory cell chemotaxis and proliferation. [2][3][4] Studies have also demonstrated that Ang II activation of the angiotensin type 1 receptor (AT 1 ) results in an increase in the inflammatory cytokine tumor necrosis factor (TNF) ␣ in a rat model of unilateral ureteral obstruction. 5 Ang II also regulates the activation of nuclear factor B and stimulates the production of chemokines, such as monocyte chemoattractant protein-1 (MCP-1), and cytokines, such as interleukin 6 and interleukin 8. 4,6,7 Thus, Ang II is not only an important component in the regulation of blood pressure but is also involved in the inflammation that accompanies hypertension.Epoxyeicosatrienoic acids (EETs) have been shown to contribute to vascular tone and improve endothelial function. 8 In the Ang II model of salt-sensitive hypertension, renal EET production is inappropriately decreased. Cyp2c enzymes are the major EET-forming enzymes in the kidney, 9 and EET production can be altered by changes in the expression and activity of these enzymes....

Aims/hypothesis Animal models of diabetic nephropathy show increased levels of glomerular vascular endothelial growth factor (VEGF)-A, and several studies have shown that inhibiting VEGF-A in animal models of diabetes can prevent albuminuria and glomerular hypertrophy. However, in those studies, treatment was initiated before the onset of kidney damage. Therefore, the aim of this study was to investigate whether transfecting mice with the VEGF-A inhibitor sFlt-1 (encoding soluble fms-related tyrosine kinase 1) can reverse pre-existing kidney damage in a mouse model of type 1 diabetes. In addition, we investigated whether transfection with sFlt-1 can reduce endothelial activation and inflammation in these mice. Methods Subgroups of untreated 8-week-old female C57BL/ 6J control (n = 5) and diabetic mice (n = 7) were euthanised 5 weeks after the start of the experiment in order to determine the degree of kidney damage prior to treatment with sFLT-1. Diabetes was induced with three i.p. injections of streptozotocin (75 mg/kg) administered at 2 day intervals. Diabetic nephropathy was then investigated in diabetic mice transfected with sFlt-1 (n = 6); non-diabetic, non-transfected control mice (n = 5); non-diabetic control mice transfected with sFlt-1(n = 10); and non-transfected diabetic mice (n = 6). These mice were euthanised at the end of week 15. Transfection with sFlt-1 was performed in week 6. Results We found that transfection with sFlt-1 significantly reduced kidney damage by normalising albuminuria, glomer-ular hypertrophy and mesangial matrix content (i.e. glomeru-lar collagen type IV protein levels) (p < 0.001). We also found that transfection with sFlt-1 reduced endothelial activation (p < 0.001), glomerular macrophage infiltration (p < 0.001) and glomerular TNF-α protein levels (p < 0.001). Finally, sFLT-1 decreased VEGF-A-induced endothelial activation in vitro (p < 0.001). Conclusions/interpretation These results suggest that sFLT-1 might be beneficial in treating diabetic nephropathy by inhibiting VEGF-A, thereby reducing endothelial activation and glomerular inflammation, and ultimately reversing kidney damage.

Abstract-Obesity and hypertension have been identified as cardiovascular risk factors that contribute to the progression of end-stage renal disease. To examine the mechanisms by which a high-fat diet and hypertension contribute to endothelial dysfunction and renal injury, 8-week-old male spontaneously hypertensive rats and Wistar rats were fed a high-fat (36% fat) or a normal-fat (7% fat) diet for 10 weeks. The high-fat diet increased body weight in Wistar and hypertensive rats by 25 and 31 g, respectively. Systolic blood pressure was higher in the hypertensive rats compared with Wistar rats; however, blood pressure was unaltered by the high-fat diet. Afferent arteriole response to acetylcholine was impaired in the high-fat groups after just 3 weeks. Renal macrophage infiltration was increased in the hypertensive high-fat group compared with others, and monocyte chemoattractant protein-1 excretion was increased in both of the high-fat-fed groups. Renal PCR arrays displayed significant increases in 2 inflammatory genes in hypertensive rats fed a normal diet, 1 gene was increased in high-fat-fed Wistar rats, whereas 12 genes were increased in high-fat-fed hypertensive rats. Urinary albumin excretion was increased in the hypertensive rats compared with the Wistar rats, which was further exacerbated by the high-fat diet. Glomerular nephrin expression was reduced and desmin was increased by the high-fat diet in the hypertensive rats. Our results indicate that endothelial dysfunction precedes renal injury in normotensive and spontaneously hypertensive rats fed a high-fat diet, and hypertension with obesity induces a powerful inflammatory response and disruption of the renal filtration barrier. Key Words: obesity Ⅲ inflammation Ⅲ hypertension Ⅲ renal disease O besity and hypertension are comorbid pathological conditions that have been identified as independent risk factors for the development of endothelial dysfunction and renal disease. 1 These risk factors are increasing in prevalence at an alarming rate, with Ͼ30% of the US population classified as obese, and 1 in 3 adult Americans currently suffering from hypertension. Blood pressure is strongly correlated with body mass index, and in the Framingham Offspring Study, Յ78% of male hypertensive cases were attributable to obesity. 2 Independently obesity increases the risk for chronic kidney disease 4-fold, 3 hypertensive patients account for 25% of all chronic kidney disease patients, and obese patients with hypertension are at the greatest risk for developing chronic renal disease. 4 -6 Independently, hypertension and obesity have been linked with the development of insulin resistance, endothelial dysfunction, inflammation, and renal injury. 7,8 However, these conditions are commonly found in combination, and it is now becoming apparent that the ensuing renal injury and vascular dysfunction are results of the combination of the 2 risk factors. 9 Animal models of obesity and hypertension, such as the obese Zucker rat, have been shown to develop albuminuria, progress...

Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules.

Nitric oxide is a pro-natriuretic and pro-diuretic factor. The highest renal nitric oxide synthase (NOS) activity is found in the inner medullary collecting duct (IMCD). The collecting duct (CD) is the site of daily fine-tune regulation of sodium balance, and led us to hypothesize that a CD specific deletion of NOS1 would result in an impaired ability to excrete a sodium load leading to a salt-sensitive blood pressure phenotype. We bred AQP2-CRE mice with NOS1 floxed mice to produce flox control and CD-specific NOS1 knockout (CDNOS1KO) littermates. Collecting ducts from CDNOS1KO mice produced 75% less nitrite and urinary nitrite+nitrate (NOx) excretion was significantly blunted in the knockout genotype. When challenged with high dietary sodium, CDNOS1KO mice showed significantly reduced urine output, sodium, chloride and NOx excretion, and increased mean arterial pressure relative to flox control mice. In humans, urinary NOx is a newly identified biomarker for the progression of hypertension. These findings reveal that NOS1 in the CD is critical in the regulation of fluid-electrolyte balance, and this new genetic model of CD NOS1 gene deletion will be a valuable tool to study salt-dependent blood pressure mechanisms.