Fluvastatin Ameliorates Podocyte Injury in Proteinuric Rats via Modulation of Excessive Rho Signaling

Shibata, Shigeru; Nagase, Miki; Fujita, Toshiro

doi:10.1681/asn.2005050571

Cited by 105 publications

(111 citation statements)

References 48 publications

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“…40 Statins have been shown to ameliorate tubular and podocyte injury, preserve GFR and reduce proteinuria in renal disease. 41,42 In the present study, although all subjects were already treated with the maximal recommended dose of the ARB olmesartan, and there was no significant difference in the number of patients treated by statins at baseline between the two groups, further reduction in high-sensitivity CRP, urinary 8-OHdG and L-FABP levels was obtained. This suggests that additive azelnidipine therapy may be beneficial in patients with albuminuria or higher levels of urinary 8-OHdG and L-FABP excretion.…”

Section: Discussionmentioning

confidence: 44%

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

et al. 2011

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The present study aimed to determine whether either of two calcium channel blockers affected urinary albumin excretion or urinary levels of 8-hydroxy-2¢-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) in hypertensive diabetic patients with chronic kidney disease (CKD) who were already being treated with maximum doses of the angiotensin II receptor blocker olmesartan. We conducted an open-label, randomized, parallel-controlled study on type 2 diabetic patients with stable glycemic control who were receiving fixed doses of antidiabetic agents. The patients received either 8 mg per day azelnidipine, which was increased up to 16 mg per day (azelnidipine group; n¼34), or 2.5 mg per day amlodipine, which was increased up to 5 mg per day (amlodipine group; n¼33), over a 24-week period. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, whereas the urinary albumin/creatinine ratio and 8-OHdG and L-FABP levels decreased significantly in the azelnidipine group compared with the amlodipine group. Plasma aldosterone level was significantly decreased in the azelnidipine group, and its changes correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of azelnidipine to the maximal recommended dose of olmesartan was more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than the addition of amlodipine. Hypertension Research (2011) 34, 935-941; doi:10.1038/hr.2011.67; published online 9 June 2011 Keywords: aldosterone; calcium channel blocker; chronic kidney disease; diabetic nephropathy; oxidant stress INTRODUCTIONThe importance of strict blood pressure (BP) control in patients with chronic kidney disease (CKD) was emphasized by the Japanese Society of Hypertension recommendations of a target BP of o130/ 80 mm Hg for hypertensive patients with CKD. This target is further reduced to o125/75 mm Hg for diabetic nephropathy patients whose urinary protein excretion is 41 g per day. 1 Reduction in proteinuria using suitable therapeutic interventions, similar to renin-angiotensin system (RAS) blockade an antihypertensive treatment regimen, is associated with a slower decline in renal function compared with other treatment groups with similar BPs. 2,3 RAS blockade with angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers (ARBs) is currently considered the most effective pharmacological approach for renoprotection. These agents reduce proteinuria more effectively than other antihypertensive drugs, and therefore, RAS inhibitors should be titrated to maximal recommended doses. 1,4 However, it is difficult to control BP with mono-

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Section: Discussionmentioning

confidence: 44%

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

et al. 2011

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“…In cultured mouse podocytes, filamentous actin reorganization by mechanical stretch was dependent on Rhokinase, a major downstream target of RhoA (49). Pharmacological inhibitors of Rho-kinase have been shown to ameliorate proteinuria and/or kidney functions in a variety of animal models of kidney diseases, including puromycin aminonucleoside nephrosis (50,51) and hypertensive glomerulosclerosis (52)(53)(54)(55)(56). These effects were independent of systemic blood pressure, suggesting that the inhibitors act directly in the kidney, in particular on podocytes (52)(53)(54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Mouawad

Aoudjit

Jiang

et al. 2014

Journal of Biological Chemistry

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Background: Disruption of the actin cytoskeleton-dependent structural integrity of glomerular epithelial cells (GEC) leads to glomerular dysfunction. Results: We have identified molecular mechanisms through which the injury-causing complement complex induces cytoskeletal changes in GEC. Conclusion: Complement-induced activation of the ERK/GEF-H1/RhoA pathway protects GEC from cell death. Significance: This study furthers our understanding of mechanisms underlying GEC foot process effacement and functional impairment in immune mediated glomerular diseases.

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“…Vascular injury score was semiquantitated as 0, 1ϩ, 2ϩ, and 3ϩ according to the criteria by Ishimitsu et al 26 Tubulointerstitial injury score was graded into 0, 0%; 1ϩ, 1% to 10%; 2ϩ, 11% to 25%; 3ϩ, 26% to 50%; 4ϩ, 51% to 75%; and 5ϩ, 76% to 100%, according to the scoring system reported previously with some modification. 25 All of the morphometric measurements were performed by 2 examiners without knowledge of the treatment protocol (nϭ4 per group).…”

Section: Histological Analysismentioning

confidence: 99%

“…25,27 Immunostaining for B7-1 and WT-1 was performed using mouse anti-rat B7-1 (3H5, 1:50, BD Pharmingen, San Diego, CA) and rabbit anti-human WT-1 (1:500, Santa Cruz Biotechnology, California, CA) after antigen retrieval. For B7-1, sections were processed with biotinyl tyramide.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

et al. 2006

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Abstract-Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.

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Fluvastatin Ameliorates Podocyte Injury in Proteinuric Rats via Modulation of Excessive Rho Signaling

Cited by 105 publications

References 48 publications

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

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