Abstract-The objective of this study was to determine the effect of pioglitazone on blood pressure (BP) and oxidative balance in obese, hypertensive, Sprague-Dawley rats and to identify some of the molecular mechanisms involved. After 12 weeks of a moderately high-fat diet, rats diverged into obesity-prone (OP) and obesity-resistant (OR) groups (nϭ6 per group). At the end of the diet, peroxisome proliferator activated receptor-␥ (PPAR␥) mRNA expression and activity in the renal cortex and medulla of OP rats were significantly lower compared with that in OR rats. Pioglitazone treatment increased PPAR␥ expression and activity in OP rats, suggesting a possible direct ligand-related effect of pioglitazone. As opposed to the untreated OP group, which showed moderate hypertension (systolic BPϭ159Ϯ5.3 mm Hg) after 12 weeks, pioglitazone-treated rats were normotensive (systolic BPϭ123.9Ϯ2.7 mm Hg). Insulin production was reduced by 2-fold in the OP group treated with pioglitazone. Urinary isoprostanes and renal lipid peroxides were also reduced in OP rats treated with pioglitazone compared with untreated counterparts. Also, expression of p47phox and gp91phox, both increased in OP versus OR rats, was reduced in the former by pioglitazone treatment. In addition, pioglitazone treatment increased nitrate/nitrite excretion and expression of renal endothelial and neuronal nitric oxide synthase. Collectively, the results show that pioglitazone treatment prevented hypertension and renal oxidative stress both by reducing free-radical production and by increasing nitric oxide production/availability. Key Words: kidney Ⅲ oxidative stress Ⅲ free radicals Ⅲ nitric oxide Ⅲ vitamins O besity is a widespread and increasingly prevalent condition associated with a large number of comorbid diseases, one of the most important of which is obesityinduced hypertension. A pleiotropic class of molecules involved in regulation of gene expression in a variety of metabolic and cardiovascular conditions is the peroxisome proliferator-activated receptors (PPARs). PPARs are ligandactivated transcription factors that form heterodimers with the 9-cis retinoic acid receptor RXR␣. 1 PPAR␥ is one of the three PPAR isoforms and is one of the major regulators of adipogenesis. 2 In addition, PPAR␥ exerts pleiotropic effects on blood pressure, lipid metabolism, and insulin action.Recent genetic analysis showed that 2 dominant-negative mutations in PPAR␥ were associated with severe hypertension in humans. 3,4 Consistent with these findings, thiazolidinendiones, the insulin-sensitizer drugs (pioglitazone, rosiglitazone) that are also high-affinity PPAR␥ ligands, 5 have been shown to lower blood pressure (BP) in a variety of hypertensive animal models 6 -8 as well as in diabetic and nondiabetic, 9 hypertensive humans. However, the mechanism underlying the antihypertensive effects of PPAR␥ agonists is not known. PPAR␥ and RXR have been found constitutively expressed in the inner medullary collecting ducts, thick ascending limb, glomerulus, and renal medullary mic...

Severe renal ischemia-reperfusion injury (IRI) can lead to acute and chronic kidney dysfunction. Cytoskeletal modifications are among the main effects of this condition. The majority of studies that have contributed to the current understanding of IRI have relied on histological analyses using exogenous probes after the fact. Here we report the successful real-time visualization of actin cytoskeletal alterations in live proximal and distal tubules that arise at the onset of severe IRI. To achieve this, we induced fluorescent actin expression in these segments in rats with hydrodynamic gene delivery (HGD). Using intravital two-photon microscopy we then tracked and quantified endogenous actin dysregulation that occurred by subjecting these animals to 60 min of bilateral renal ischemia. Rapid (by 1-h post-reperfusion) and significant (up to 50%) declines in actin content were observed. The decline in fluorescence within proximal tubules was significantly greater than that observed in distal tubules. Actin-based fluorescence was not recovered during the measurement period extending 24 h post-reperfusion. Such injury decimated the renal architecture, in particular, actin brush borders, and hampered the reabsorptive and filtrative capacities of these tubular compartments. Thus, for the first time, we show that the combination of HGD and intravital microscopy can serve as an experimental tool to better understand how IRI modifies the cytoskeleton in vivo and provide an extension to current histopathological techniques.

Recent evidence suggests that hypertension in the Okamoto spontaneously hypertensive rat (SHR) may be the result of an autoimmune disorder. To test this hypothesis SHRs were given chronic immunosuppressive therapy (cyclophosphamide). The development of spontaneous hypertension was studied in SHRs receiving cyclophosphamide beginning at age 3 wk. The arterial pressure of the cyclophosphamide-treated SHRs was significantly lower than that of untreated control SHRs once the rats were 8 wk old, and this reduction in blood pressure was maintained for the duration of treatment. Also the effect of chronic immunosuppressive therapy on the maintenance of spontaneous hypertension was determined by beginning treatment in 16-wk-old SHRs. Arterial pressure was significantly less than that of untreated control SHRs after 2 wk of treatment. According to tail-cuff measurements, the level of hypertension in the SHRs was reduced by approximately 50% following 6 wk of immunosuppressive therapy. The mean arterial pressure was significantly reduced after 6 wk to 158 +/- 5.0 mmHg in immunosuppressed SHRs (n = 10) compared with 174 +/- 2.6 mmHg in control SHRs (n = 7). Cyclophosphamide treatment did not have a significant effect on the blood pressure of Wistar or Wistar-Kyoto rats or on the development or maintenance of deoxycorticosterone acetate hypertension. Chronic immunosuppression attenuates hypertension in the Okamoto SHR. These results support the hypothesis that spontaneous hypertension may be due in part to an autoimmune disorder.

The objective of these experiments was to study pressure natriuresis in the Wistar-Kyoto (WKY) and the spontaneously hypertensive rat (SHR) during acute bilateral renal decapsulation, a maneuver that partially blocks the increase in renal interstitial hydrostatic pressure (RIHP). In control WKY rats (n = 7), at renal perfusion pressure (RPP) of 105 +/- 0.7 and 125 +/- 1.1 mmHg, RIHP increased from 4.4 +/- 0.4 to 7.2 +/- 0.7 mmHg (P less than 0.05) and fractional excretion of sodium (FENa) increased from 0.23 +/- 0.05 to 1.32 +/- 0.14% (P less than 0.05). Acute bilateral renal decapsulation (n = 6) blunted the increase in RIHP observed when RPP was increased in control WKY rats and abolished the pressure natriuretic and diuretic response. When RPP was allowed to increase from 106 +/- 0.8 to 130 +/- 2.2 mmHg in the WKY rats with decapsulated kidneys, RIHP increased from 3.8 +/- 0.5 to 4.3 +/- 0.4 mmHg but FENa did not significantly change (0.31 +/- 0.12 to 0.43 +/- 0.13%). In control SHRs (n = 7), at RPPs of 135 +/- 0.8 and 163 +/- 3.0 mmHg, RIHP was 4.4 +/- 0.4 and 5.0 +/- 0.6 mmHg (NS) and FENa was 0.41 +/- 0.10 and 0.82 +/- 0.17% (P less than 0.05). Renal decapsulation in the SHR did not affect the blunted relationships between RPP, RIHP, and FENa; at RPPs of 135 +/- 0.3 and 162 +/- 2.9 mmHg (n = 7), RIHP was 4.4 +/- 0.6 and 4.7 +/- 0.5 mmHg (NS) and FENa was 0.43 +/- 0.10 and 0.95 +/- 0.22% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The objective of this study was to compare renal interstitial hydrostatic pressure (RIHP) and sodium excretion in female and male Sprague-Dawley (SD) rats. The RIHP and pressure natriuresis responses were determined in female (n=13) and male (n=8) SD rats. Renal perfusion pressure (RPP) was controlled at two levels (100 and 120 mm Hg). Clearances were taken at each level and RIHP was measured with a chronically implanted polyethylene matrix in all rats. At the lower RPP level, RIHP was similar in both groups of rats (5.2+/-0.2 mm Hg for female, and 5.5+/-0.4 mm Hg for male), whereas fractional excretion of sodium (FENa) was significantly lower (P < .05) in male (1.10+/-0.27%) as compared to female (2.23+/-0.32%) rats at similar lower RPP. Allowing RPP to increase from 100 to 120 mm Hg resulted in similar increases in FENa (deltaFENa), urine flow rate (deltaV), and RIHP (deltaRIHP) in both groups of rats. The deltaFENa, deltaV, and deltaRIHP were 1.67+/-0.43%, 38.45+/-4.74 microL/min/g kidney weight, and 2.7+/-0.2 mm Hg for female, and 1.79+/-0.42%, 30.40+/-4.37 microl/min/g kidney weight, and 2.8+/-0.3 mm Hg for male rats. In conclusion, RIHP is similar in female and male SD rats at similar RPP levels. Both female and male SD rats increase RIHP and sodium excretion similarly in response to increases in RPP. The lower basal FENa in male as compared to female rats may play an important role in the more significant elevation of blood pressure in males with age.