Aldosterone promotes fibronectin production through a Smad2-dependent TGF-β1 pathway in mesangial cells

Lai, Lingyun; Chen, Jing; Hao, Chuan‐Ming; Lin, Song; Gu, Yong

doi:10.1016/j.bbrc.2006.07.057

Cited by 57 publications

(50 citation statements)

References 37 publications

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“…22,23 In mesangial cells aldosterone stimulates fibronectin synthesis through both TGF-β1-dependent and -independent pathways. 24 Although aldosterone had been believed to be synthesized only in the adrenal cortex, we and other researchers confirmed that the aldosterone synthase CYP11B2 gene, protein, and aldosterone production are locally present in the kidney, including tubular cells, mesangial cells and podocytes. [25][26][27][28] Inhibition of local renal aldosterone by FAD286 (aldosterone synthase inhibitor) or spironolactone (non-selective aldosterone receptor antagonist) has been shown to decrease nuclear factor kappaB (NFκB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), TGF-β1, glomerular fibronectin and collagen type IV expression in diabetic nephropathy.…”

Section: Introductionmentioning

confidence: 56%

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Sun

Rui

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Background and objective:The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression. Methods: Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/ kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (C cr ), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF-β1, CTGF and PAI-1 gene expression levels were determined. Results: On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced C cr , induced urinary proteins and up-regulated COL-I, TGF-β1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-β1 and PAI-1 up-regulation but did not improve renal function. Conclusion:Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA.

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Section: Introductionmentioning

confidence: 56%

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Sun

Rui

et al. 2014

J Renin Angiotensin Aldosterone Syst

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“…132 In vitro studies have shown that mesangial cells significantly increase production of TGFβ and fibronectin in response to aldosterone, an effect which can be mitigated by the aldosterone antagonist, spironolactone. 133 In vivo aldosterone infusion in rats significantly increases urinary TGFβ concentration and rats that have undergone uninephrectomy and receive aldosterone at the same time as AT1 blockade, showed increased expression of TGFβ and collagen, supporting that aldosterone is an independent pro-fibrotic mediator. 132,134,135 Aldosterone has also been shown to increase expression of CTGF and to increase production of ROS and inflammatory mediators such as osteopontin, IL6 and IL1.…”

Section: Activation Of the Renin-angiotensin-aldosterone Systemmentioning

confidence: 92%

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

Jepson

2016

Veterinary Clinics of North America: Small Animal Practice

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Abstract:In cats with chronic kidney disease (CKD), the most common histopathological finding is tubulointerstitial inflammation and fibrosis. However, these changes reflect a non-specific response of the kidney to any inciting injury. The risk of development of CKD in a patient is likely to reflect genetic predispositions, ageing, environmental and individual factors that influence decline in renal function over the course of a cat's life. However, there is still relatively little information about exactly which risk factors predispose a cat to develop CKD and these will be explored. Whilst many cats diagnosed with CKD have stable disease for many years, some cats show overtly progressive disease.

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“…29,33,34 The likely importance of the local glomerular RAAS relates to the pathogenesis of glomeruloscleorsis and the loss of glomerular permselectivity observed in many glomerular diseases. In cultured mesangial cells, Ang II [35][36][37] and aldosterone 38,39 provoke synthesis of extracellular matrix (ECM) proteins that accumulate in glomerulosclerosis. In podocytes, Ang II has been shown to induce apoptosis, 40,41 cytoskeletal rearrangement 42 and nephrin loss 43 in podocytes, alterations that have been linked to albuminuria.…”

Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Aldosterone promotes fibronectin production through a Smad2-dependent TGF-β1 pathway in mesangial cells

Cited by 57 publications

References 37 publications

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

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