From Finland to Fatland

Afzali, Behdad; Haydar, Ali; Vinen, Katie; Goldsmith, David

doi:10.1097/01.asn.0000133252.07149.05

Cited by 23 publications

(9 citation statements)

References 62 publications

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“…Evidence is available that statins, by lowering blood lipid concentration, reduce urinary protein excretion rate and preserve renal function in patients with chronic proteinuric nephropathies [8, 9]. Moreover, evidence has accumulated in recent years that statins have pleiotropic effects that extend beyond cholesterol-lowering activity [10, 11].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, evidence has accumulated in recent years that statins have pleiotropic effects that extend beyond cholesterol-lowering activity [10, 11]. Besides inhibiting the rate-limiting step in cholesterol synthesis, namely the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) into mevalonate, statins interfere with prenylation of Ras and Rho family small GTP-binding proteins, thereby blocking the activation of a series of signaling pathways and transcription factors which regulate the expression of inflammatory, vasoactive, and profibrotic genes critical to renal disease progression [9, 12]. In a model of passive Heymann nephritis (PHN), that mimics advanced stages of human membranous nephropathy and is not fully responsive to ACE inhibition, combining simvastatin with an ACE inhibitor afforded better renoprotection than simvastatin alone [13].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Rosuvastatin on Glomerular Capillary Size-Selectivity Function in Rats with Renal Mass Ablation

Corna

Sangalli

Cattaneo³

et al. 2007

Am J Nephrol

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Background: Evidence is accumulating that statins can reduce proteinuria and disease progression in chronic kidney disease. However, some safety concerns have been recently raised on the use of these agents, mainly due to transient episodes of proteinuria observed in patients receiving high doses of rosuvastatin. Methods: We investigated in rats with renal mass ablation (RMR) whether rosuvastatin (5 or 20 mg/day) worsens proteinuria as compared to untreated RMR animals. Moreover, we also examined whether rosuvastatin-induced changes in proteinuria would be due to the effect of the drug on permselective properties of glomerular capillary barrier, measured by the fractional clearance of graded-size Ficoll molecules and/or by proximal tubular mechanisms, by assessing urinary excretion of β₂-microglobulin. Results: RMR rats given rosuvastatin for 28 days showed a progressive increase in proteinuria, with values numerically but not significantly higher than those in RMR animals given the vehicle. In RMR rats, rosuvastatin did not significantly affect the fractional clearance of Ficoll as compared to vehicle-treated RMR animals. A significant correlation was found between urinary protein and β₂-microglobulin excretion in rats treated with rosuvastatin (r = 0.936, p < 0.001), but not in those given vehicle. Renal function, glomerular and tubulointerstitial injury were comparable in rosuvastatin-treated and untreated RMR rats at the end of the 28-day follow-up. Conclusion: In rats with RMR, rosuvastatin mildly enhances urinary protein excretion rate. This, however, was not the result of further changes in the size-permselective function of glomerular capillary barrier.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Rosuvastatin on Glomerular Capillary Size-Selectivity Function in Rats with Renal Mass Ablation

Corna

Sangalli

Cattaneo³

et al. 2007

Am J Nephrol

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“…A recent review of the effect of statins on renal function suggested that statins reduced the rate of kidney function loss by ϳ75% and reduced albuminuria by 47% in people with baseline albuminuria of Յ300 mg/dl (20 -22). Although the benefits of statins had initially been attributed to their lipidlowering effects (21,23,24), recent studies have proposed that statins have direct modulatory effects on the Rho GTPase signaling pathways (25,26). These pleiotropic, or lipid-independent, effects of statins primarily involve inhibition of the mevalonate pathway with subsequent inactivation of several signaling proteins including .…”

mentioning

confidence: 99%

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

Kolavennu

Zeng²,

Peng³

et al. 2008

Diabetes

186

167

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OBJECTIVE-RhoA, a small GTPase protein, and its immediate downstream target, Rho kinase (ROCK), control a wide variety of signal transduction pathways. Recent studies have shown that fasudil, a selective ROCK inhibitor, may play a pivotal role in a number of pathological conditions, ranging from cardiovascular diseases to pulmonary hypertension and erectile dysfunction. Considerable evidence suggests that some of the beneficial effects of statins may also stem from their modulatory effects on RhoA/ROCK signaling. In the current study, we hypothesized that pharmacological blockade of the RhoA/ROCK pathway with either fasudil or simvastatin would ameliorate progression of diabetic nephropathy. RESULTS-The kidney cortices of untreated db/db mice displayed increased ROCK activity compared with db/m mice. The fasudil-treated mice exhibited a significant reduction in ROCK activity, albuminuria, glomerular collagen IV accumulation, and urinary collagen IV excretion compared with untreated db/db mice. Interestingly, blood glucose was unaffected by fasudil administration. Treatment with simvastatin significantly attenuated RhoA activation in the kidney cortices of db/db mice and resulted in a significant reduction of albuminuria and mesangial matrix expansion. RESEARCH DESIGN AND METHODS-InCONCLUSIONS-Based on these results, we propose that RhoA/ROCK blockade constitutes a novel approach to the treatment of diabetic nephropathy. Our data also suggest a critical role for RhoA/ROCK activation in the pathogenesis of diabetic nephropathy. Diabetes 57:714-723, 2008 T he Rho family of small GTPases are 20-to 40-kDa monomeric G proteins that regulate a number of cell functions, including cytoskeletal reorganization, cell motility, and gene expression (1). They cycle between two conformational states: an active GTPbound state and an inactive GDP-bound state (2). One of the best recognized members of the Rho GTPase family is RhoA. Rho kinase (ROCK), a downstream effector of RhoA, is a serine/threonine kinase of ϳ160 kDa that exists in two isoforms in mammals: ROCK1 and ROCK2 (3). ROCK is comprised of an amino-terminal kinase domain, followed by a coiled-coil region that contains the -binding domain. The carboxy-terminal consists of a plexstrinhomology domain, which contains an internal cysteinerich domain. ROCK1 and ROCK2 are highly homologous, sharing an identity of 65% in their overall amino acid sequences and 92% in their kinase domains.The RhoA/ROCK pathway has recently received considerable attention for its involvement in a wide variety of pathological states ranging from cardiovascular disease and pulmonary hypertension to Alzheimer's disease and glaucoma (4 -7). A growing body of evidence also suggests that the RhoA/ROCK pathway may have renomodulatory effects. Indeed, several recent studies have proposed that RhoA/ROCK may play an important role in renal fibrosis by enhancing signaling pathways involving transforming growth factor-␤, angiotensin II, and nuclear factor-B (8 -10). Furthermore, since the discovery of fasudi...

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“…Hiperlipidemiklerde artmış olan monositlerin endotel hücrelere bağlanma yetenekleri lovastatin ve simvastatin kullanımı ile azalmıştır. Diyabetik hastalarda lipid düşürücü tedavinin GFR'yi koruduğu ve proteinüriyi azalttığı gösterilmiştir.Yine başka bir çalışmada 40mg simvastatinin diyabetli hastalarda major vasküler olayların oranını azalttığı ve GFR kötüleşmesini azalttığı, bunların kolesterol seviyelerinden bağımsız olduğu gösterilmiştir (13,14,15,16,17,18,19,20,21).…”

Section: Introductionunclassified

Effect of Atorvastatin Therapy on IL-6, IL-10, TNF-∝ and TGF-β in Chronic Hemodialysis Patients

Türkmen¹,

Işıtmangil²,

Berber³

et al. 2010

Turk Neph Dial Transpl

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ÖZAMAÇ: Bu çalışmanın amacı, atorvastatinin pro-ve anti-infl amatuar sistem üzerine etkisini kronik hemodiyaliz (HD) hastalarında immünolojik açıdan değerlendirmekti. GEREÇ ve YÖNTEM:Çalışmamıza düzenli HD tedavisi altındaki yaş ortalaması 48,5 ± 12,8 ve diyaliz yaşı 12,0 ± 4,3 yıl olan 31 hasta (19 erkek, 12 kadın) alındı. Haftada 3 gün Fresenius 4008-B ile 4 saat hemodiyaliz tedavisi, Fx80 ile Kt/V >1.4 olacak şekilde planlandı. Prediyaliz ve postdiyaliz hasta serumlarında IL-6, IL-10, TNF-α, TGF-β sitokin düzeyleri atorvastatin tedavisinden önce ve 8 hafta 40 mg/gün tedavi aldıktan sonra ELISA yöntemi ile çalışıldı.BULGULAR: HD girişte ve çıkışta; atorvastatin öncesi ile atorvastatin sonrası IL-6 ve IL-10 ölçümleri arasındaki fark istatistiksel olarak anlamlı bulunmamıştır (p>0,05). Hemodiyalize girişte; atorvastatin öncesi TNF-α ve TGF-β düzeyleri sonrasına göre istatistiksel olarak anlamlı düzeyde artış göstermektedir (p<0,01). HD çıkışta aynı şekilde atorvastatin öncesi TNF-α ve TGF-β düzeyleri sonrasına göre istatistiksel olarak anlamlı düzeyde artış göstermektedir (p<0,01). Atorvastatin tedavisi öncesinde hemodiyalize giriş ile çıkış IL-6 ve IL-10 ölçümleri arasındaki fark istatistiksel olarak anlamlı bulunmuştur (p<0,01). Atorvastatin tedavisi öncesinde HD giriş-çıkış TNF-α ve TGF-β ölçümleri arasındaki fark istatistiksel olarak anlamlı bulunmuştur (p<0,05). Atorvastatin tedavisi sonrasında HD giriş-çıkış IL-6 ve IL-10 ölçümleri arasındaki fark istatistiksel olarak anlamlı bulunmuştur (p<0,01). Atorvastatin tedavisi sonrasında hemodiyalize giriş-çıkış TNF-α ve TGF-β ölçümleri arasındaki fark istatistiksel olarak anlamlı değildir (p>0,05). SONUÇ:Hemodiyaliz etkisi ile proenfl amatuvar sitokinlerde (IL-6 ve TNF-α) ve antienfl amatuvar sitokinlerde (IL-10 ve TGF-β) istatistiksel olarak anlamlı artış meydana gelmesine rağmen atorvastatin kullanımı ile yalnızca TNF-α ve TGF-β'daki hemodiyalize bağlı yükselme baskılanmıştır. Önemli bir proinfl amatuar sitokin olan TNF-α'nın baskılanması, atorvastatinin anti-infl amatuar etkisini desteklemesi yönünden önem taşımaktadır.ANAHTAR SÖZCÜKLER: Hemodiyaliz, Atorvastatin, Sitokin ABSTRACT OBJECTIVE: We aimed to compare serum cytokine levels of IL-6, IL-10, TNF-α and TGF-β before and after atorvastatin therapy in chronic hemodialysis (HD) patients in order to detect infl ammatory and anti-infl ammatory effects of atorvastatin in this study. MATERIAL and METHODS:Thirty-one patients (19 male, 12 female) undergoing continuous hemodialysis with a mean age 48.5+12.8 and dialysis age 12+4.3 years were included in our study. HD was planned as 3 days a week with Fresenius 4008-B during 4 hours, FX80 with Kt/V >1.4. We measured the serum cytokine levels of the patients with the ELISA technique, before atorvastatin therapy and after 40 mg/day atorvastatin administration during 8 weeks. RESULTS:Hemodialysis leads to a statistically signifi cant increase in proinfl ammatory cytokines (IL-6 and TNF-α) and antiinfl ammatory cytokines (IL-10 ve TGF-β). However, atorvastatin therapy a...

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From Finland to Fatland

Cited by 23 publications

References 62 publications

Effects of Rosuvastatin on Glomerular Capillary Size-Selectivity Function in Rats with Renal Mass Ablation

Effects of Rosuvastatin on Glomerular Capillary Size-Selectivity Function in Rats with Renal Mass Ablation

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

Effect of Atorvastatin Therapy on IL-6, IL-10, TNF-∝ and TGF-β in Chronic Hemodialysis Patients

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