These findings suggest that abnormal HDL capacity to mediate cholesterol efflux is a key driver of excess CVD in patients on chronic hemodialysis and may explain why statins have limited effect to decrease CV events. The findings also suggest cellular cholesterol transporters as potential therapeutic targets to decrease CV risk in this population.

Objective-Peroxisome proliferator-activated receptor gamma (PPAR␥) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis. Methods and Results-To investigate the contribution of macrophage PPAR␥ expression on atherogenesis in vivo, we generated macrophage-specific PPAR␥ knockout (MacPPAR␥KO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor-deficient (LDLR Ϫ/Ϫ ) mice were reconstituted with MacPPAR␥KO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPAR␥KO and wild-type marrow. In contrast, both C57BL/6 and LDLR Ϫ/Ϫ mice transplanted with MacPPAR␥KO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPAR␥KO3 LDLR Ϫ/Ϫ mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPAR␥KO mice had decreased uptake of oxidized but not acetylated LDL and showed no changes in either cholesterol efflux or inflammatory cytokine expression. Macrophages from MacPPAR␥KO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages. Conclusion-Thus, macrophage PPAR␥ deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPAR␥, which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment. Key Words: ABCA1 Ⅲ atherosclerosis Ⅲ CCR2 expression Ⅲ cholesterol efflux Ⅲ macrophages Ⅲ scavenger receptor CD36 P eroxisome proliferator-activated receptor gamma (PPAR␥) is a nuclear transcription factor that regulates a large number of genes important in lipid metabolism and inflammation. 1 The receptor is highly expressed in macrophages and macrophage-derived foam cells of atherosclerotic lesions, 2-4 and its expression may critically affect macrophage functions that impact atherosclerosis, including activation, cytokine production, recruitment, and transformation into foam cells.Several studies have shown that the administration of PPAR␥ agonists inhibits the development of atherosclerosis in low-density lipoprotein (LDL) receptor-deficient (LDLR Ϫ/Ϫ ) 5,6 and apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. 7 Consistent with this, mice transplanted with bone marrow from a PPAR␥ Ϫ/Ϫ chimera mouse exhibit a significant increase in atherosclerosis. 8 These data all support an antiatherogenic role for macrophage PPAR␥ in atherosclerotic lesion development.It has been assumed that the antiatherogenic effects of macrophage PPAR␥ expression may derive from activation of genes responsible for cholesterol efflux, thus shifting the balance from lipid loading to lipid efflux. 8 Recent studies, however, have not confirmed the role of PPAR␥ ligands in cholesterol efflux by macrophages. 9,10 PPAR␥ may also exert antiinflammatory effects in macrophages directly, 11 or through ...

In Munich-Wistar rats, a micropipette was inserted into a first-order branch of the left main renal artery and continuously infused with human/porcine endothelin (0.4 ng/min). Micropuncture measurements revealed substantial differences within the cortical microcirculation of the same left kidney: SNGFR was some 35% lower in glomeruli exposed to endothelin compared with non-endothelin-perfused glomeruli (P < 0.005). Similarly, glomerular plasma flow rate was some 38% lower in the endothelin-exposed glomeruli (P < 0.001). The hypoperfusion and hypofiltration in the endothelin-exposed glomeruli reflected an increase in resistances in the afferent and efferent arterioles. There was no difference in the value of the glomerular capillary ultrafiltration coefficient between the two populations of glomeruli.We also studied kidneys that underwent 25 min of renal artery clamping 48 h before study. Antiendothelin antibody infused into one of the branches of the main renal artery ameliorated the vasoconstriction characteristic of postischemic nephrons: within the cortical microcirculation, the SNGFR in glomeruli exposed to antiendothelin antibody was 27.0±3.1 nl/min as compared with 17.4±1.7 measured in glomeruli not perfused with the antibody (P < 0.001). Similarly, glomerular plasma flow rate was higher in the glomeruli exposed to antiendothelin antibody (128.7±14.4 nl/min vs. 66.6±5.6, P < 0.005). Resistances in both the afferent and efferent arterioles were substantially lower in the antibody-exposed glomeruli. It is, therefore, suggested that endothelin, presumably released from damaged endothelium, may play an important intermediary role in the hypoperfusion and hypofiltration observed in postischemic kidneys. Introduction Vasomotor tone is controlled by dynamic interplay of neurogenic and myogenic mechanisms and circulating hormones. In the last several years, evidence has accumulated that the endothelium elaborates both vasoconstrictive and vasodilative substances, thereby participating in this dynamic regulation of vascular tone MethodsAll experiments were done in male Munich-Wistar rats weighing 180-230 g. The animals were allowed access to standard rat chow and tap water until the day ofthe experiment. Group 1 animals consisted of seven normal rats. The animals were prepared for micropuncture as previously described (4-6). Briefly, under anesthesia (70 mg Inactin/kg body wt i.p.; BYK, FRG) tracheostomy was performed and indwelling polyethylene catheters were inserted into the femoral artery and vein and jugular vein for blood sampling, monitoring of systemic blood pressure, infusion of plasma, and inulin as previously described (4-6). In addition, one ofthe main branches ofthe left main artery was gently isolated. Care was taken not to disrupt the renal nerves and lymphatics. This branch vessel was momentarily (< 5 s) occluded with fine forceps and distribution of its blood flow was marked on the surface of the kidney with a permanent ink marker by noting the blanching of the kidney surface. Using micro...

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.

Since recent studies indicate that cyclosporine (CsA) disrupts endothelial integrity and that injured endothelial cells release excess endothelin, we examined endothelin's role in acute cyclosporine nephrotoxicity. Following CsA (20 mg/kg i.v.), rabbit anti-porcine endothelin (aE) serum was continuously infused into a first order branch of the main renal artery in Munich-Wistar rats whereupon the hemodynamics of glomeruli not infused with aE as well as those infused with aE within the same kidney were simultaneously assessed by micropuncture techniques. In CsA treated kidneys, in glomeruli not infused with aE, single nephron GFR (SNGFR) and glomerular plasma flow rate (QA) fell profoundly (on average by 42 and 48%, respectively) below the baseline values in association with lower glomerular capillary pressure and elevated afferent arteriolar resistance. By contrast, in glomeruli infused with aE within the same CsA treated kidneys, this vasoconstrictive pattern was markedly attenuated: SNGFR was, on average, only 19% lower than baseline and values for QA as well as other parameters determining glomerular filtration were at or near the levels observed before administration of CsA. In another group of rats (N = 6) an identical dose of CsA was given to measure the circulating level of endothelin. In these CsA treated rats, endothelin level (measured by radioimmunoassay) was elevated at 41.7 +/- 14.7 pg/ml, contrasting the value of less than 2 pg/ml uniformly observed in identically instrumented normal rats not given CsA (N = 5). Thus, cyclosporine is a potential inducer for endothelin release and endothelin appears to have a pivotal role in pathophysiology of cyclosporine-induced acute renal vasoconstriction and glomerular dysfunction.

Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE 2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11β-hydroxysteroid dehydrogenase type II (11βHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc +/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11βHSD2 inhibited COX-2-mediated PGE 2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11βHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11βHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.

We studied the effects of interruption of the renin-angiotensin system (RAS) in rats that were volume depleted by water deprivation for 48 hours (AWD) with/without furosemide (AWD + F), a condition known to activate RAS. Following baseline micropuncture, AWD rats (N = 6) were treated with a specific angiotensin II type 1 receptor antagonist (AIIRA; 4 mg/kg body wt bolus i.v. and then continuous infusion) and glomerular hemodynamics compared to those obtained during angiotensin I converting enzyme inhibitor treatment (ACEI; 24 mg/kg bolus i.v. and then continuous infusion). Systemic blood pressure decreased equally following AIIRA and ACEI. Single nephron glomerular filtration rate (SNGFR) increased from baseline following AIIRA (24 nl/min vs. 30, P < 0.025). While a decrease in efferent arteriolar resistance (RE) reduced glomerular capillary pressure (PGC; 67 mm Hg vs. 60, P < 0.05), this change in RE together with decrease in afferent arteriolar resistance (RA), enhanced glomerular plasma flow rate (QA; 80 nl/min vs. 111). Antagonizing angiotensin II receptor increased QA which, together with the tendency to increase glomerular capillary ultrafiltration coefficient, Kf, served to improve glomerular filtration. By contrast, although inhibition of the angiotensin I converting enzyme caused greater vasodilatation, no increase in SNGFR occurred. The lack of response in filtration after ACEI was due to a further fall in PGC to 52 mm Hg (P < 0.01 vs. AIIRA), reflecting profound reduction in RE. Since ACEI but not AIIRA potentiates bradykinin activity we examined effects of a specific bradykinin antagonist (Hoe).(ABSTRACT TRUNCATED AT 250 WORDS)

The present study demonstrates that podocyte-restricted expression of HIV-1 gene products is sufficient for the development of collapsing glomerulosclerosis in the setting of susceptible genetic background.