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The role of circulating, systemic TGF-[beta] levels in endothelial function is not clear. TGF-[[beta].sub.1] may cause endothelial dysfunction in apolipoprotein E-deficient ([apoE.sup.-/-]) mice via stimulation of reactive oxygen species (ROS) production by the NADPH oxidase (NOX) system and aggravate aortic and heart remodeling and hypertension. Thoracic aorta (TA) were isolated from 4-too-old control (C57B1/6), [apoE.sup.-/-], TGF-[[beta].sub.1]-overexpressing (TGF[[beta].sub.1]), and crossbred [apoE.sup.-/-] x TGF[[beta].sub.1] mice. Endothelium-dependent relaxation was measured before and after incubation with apocynin (NOX inhibitor) or superoxide dismutase (SOD; ROS scavenger). Superoxide production within the vessel wall was determined by dihydroethidine staining under confocal microscope. In 8-too-old mice, aortic and myocardial morphometric changes, plaque formation by en face fat staining, and blood pressure were determined. Serum TGF-[[beta].sub.1] levels (ELISA) were elevated in TGF[[beta].sub.1] mice without downregulation of TGF-[beta]-I receptor (immunohistochemistry). In the aortic wall, superoxide production was enhanced and NO-dependent relaxation diminished in [apoE.sup.-/-] x TGF[[beta].sub.1] mice but improved significantly after apocynin or SOD. Myocardial capillary density was reduced, fibrocyte density increased, aortic wall was thicker, combined lesion area was greater, and blood pressure was higher in the [apoE.sup.-/-] x TGF[beta] vs. C57B1/6 mice. Our results demonstrate that elevated circulating TGF-[[beta].sub.1] causes endothelial dysfunction through NOX activation-induced oxidative stress, accelerating atherosclerosis and hypertension in [apoE.sup.-/-] mice. These findings may provide a mechanism explaining accelerated atherosclerosis in patients with elevated plasma TGF[[beta].sub.1]. aorta; oxidative stress; nicotinamide adenine dinucleotide phosphate; transforming growth factor-[beta]; apolipoprotein E-deficient mice doi: 10.1152/ajpheart.01042.2009.

Renal injury is accompanied by the presence of infiltrating inflammatory cells in the glomerulus and tubulointerstitium. FTY720 modifies lymphocyte migration into injured tissues by lymphocyte sequestration to secondary lymphoid organs. The purpose of this study was to examine the potential of FTY720 to influence the inflammatory response in a nonimmunological model of renal failure. Sham-operated and 5/6 nephrectomized (SNX) Sprague-Dawley rats received two different doses of FTY720 or vehicle orally for 14 wk. Treatment with FTY720 reduced glomerular and tubulointerstitial damage in SNX rats but failed to stabilize creatinine clearance. The increase in gene expression of chemokine receptors CCR1, CCR2, and CCR5 in kidneys of vehicle-treated SNX rats was significantly attenuated by high-dose FTY720. Treatment with high-dose FTY720 tended to normalize RANTES and MCP-1 renal gene expression. FTY720 affected not only glomerular and tubulointerstitial lymphocytes, but M1 and M2 phenotype macrophages were also reduced. FTY720 significantly reduced key mediators of renal inflammation and fibrosis. FTY720 also decreased immunoregulation of M2 macrophages, which are beneficial for tissue remodeling and repair. inflammatory cell filtration

Angioten-sin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin 1I. The purpose of this study was to assess the relative ability of an angiotensin receptor type I (A[T.sub.1]) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle- and dihydralazine-treated groups but was significantly lowered in the SNX+losartan as well as in the SNX+losartan+spironolactone groups and had not progressed further in the SNX+spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats alter high-dose A[T.sub.1] receptor blockade. Nonhyperkalemic doses of spironotactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the A[T.sub.1] blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis. aldosterone escape: renin-angiotensin system

Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX + R-568, SNX + calcitriol, SNX + vehicle, sham-op + R-568, sham-op + calcitriol, and sham-op + vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum- and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 [+ or -] 1.46 vs. 2.70 [+ or -]0.91 [mm.sup.3), podocyte volume (831 [+ or -] 127 vs. 397 [+ or -] 67 [micro][m.sup.3]), the degree of foot process fusion (mean width of foot processes = 958 [+ or -] 364 vs. 272 [+ or -] 35 nm), and glomerular basement membrane thickness (244 [+ or -] 6 vs. 267 [+ or -] 23nm), as well as desmin staining, were significantly higher in vehicletreated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage. secondary hyperparathyroidism; chronic renal failure; nephroprotection; calcimimetics; calcitriol

1,25[(OH).sub.2][D.sub.3] has antiproliferative effects and promotes cell differentiation. This consideration has provided the rationale for studies in subtotally nephrectomized rats showing that 1,25[(OH).sub.2][D.sub.3] intefferred with glomerulosclerosis. The cellular mechanisms involved have remained obscure, however. It was the purpose of the present study to assess glomerular structure and cellular composition in subtotally nephrectomized (SNX) rats treated with nonpharmacological doses of 1,25[(OH).sub.2][D.sub.3]. Male Sprague-Dawley rats were sham operated (sham) or underwent SNX under general anesthesia and received either solvent or 1,25[(OH).sub.2][D.sub.3] (3 ng x 100 g body [wt.sub.-1] x [day.sub.-1] sc). Blood pressure (BP) and albuminuria were measured. After 16 wk, the remnant renal tissue was perfusion fixed and morphometric and stereological measurements were carried out. The expression of proliferating cellular antigen (PCNA), cyclin-dependent kinase inhibitor p27, Wilms tumor gene (WT1), and desmin, a marker of early podocyte damage, was investigated by immunohistology. BP, serum creatinine, and urinary albumin excretion were significantly higher in SNX than in sham rats. Albuminuria was significantly lower in SNX+1,25[(OH).sub.2][D.sub.3] compared with SNX+solvent rats. Mean glomerular tuft volume was significantly higher in SNX+solvent (2.69 [+ or -] 0.21 x [10.sub.6] [micro][m.sub.3]) than in sham rats (1.44 [+ or -] 0.17 and 1.28 [+ or -] 0.14 x [10.sub.6] [micro][m.sub.3]); it was significantly (P < 0.05) lower in SNX+1,25[(OH).sub.2][D.sub.3] rats (1.81 [+ or -] 0.16 x [10.sub.6] [micro][m.sub.3]). The main finding was a significantly higher number of podocytes in SNX+1,25[(OH).sub.2][D.sub.3] (88 [+ or -] 9) and sham (98 [+ or -] 17) compared with SNX+solvent rats (81 [+ or -] 8.7). In parallel, the increase in podocyte volume in SNX+solvent rats was abrogated by treatment with 1.25[(OH).sub.2][D.sub.3], and immunohistochemistry revealed less expression of desmin, PCNA, and p27, suggesting less podocyte injury and activation of the cyclin cascade. This study identifies the podocyte as an important target cell for the renoprotective action of 1,25[(OH).sub.2][D.sub.3]. This notion is suggested by less evidence of podocyte injury, decreased podocytes loss, and abrogation of podocyte hypertrophy, findings that may also explain less pronounced albuminuria and glomerulosclerosis. visceral glomerular epithelial cell; mesangial cell; glomerular endothelial cell; progression