Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney.

Lee, L K; Meyer, Timothy W.; Pollock, Allan S.; Lovett, David H.

doi:10.1172/jci118143

Cited by 191 publications

(127 citation statements)

References 47 publications

(63 reference statements)

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“…It has been suggested that ANG II induces glomerular injuries through renal hemodynamic effects and stimulation of growth and extracellular matrix production by glomerular cells (30). Several studies on this subject have been published (4,(31)(32)(33), and several factors such as TGF-␤ and endothelin-1 have been identified as crucial components in the mechanism, but the detailed signaling mechanism responsible for the effects are largely unknown. PI3K, in the mesangial context, has been reported to induce proliferation (34), enhance collagen expression (24), and prevent apoptosis (36,37).…”

Section: Discussionmentioning

confidence: 99%

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

Yano

Suzuki

Endoh

et al. 2007

Journal of Biological Chemistry

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Chronic activation of the angiotensin II (ANG II) type 1 receptor (AT-1R) is critical in the development of chronic kidney disease. ANG II activates mesangial cells (MCs) and stimulates the synthesis of extracellular matrix components. To determine the molecular mechanisms underlying the induction of MC collagen, a mouse mesangial cell line MES-13 was employed. ANG II treatment induced an increase in collagen synthesis, which was abrogated by cotreatment with losartan (an AT-1R antagonist), wortmannin (a phosphoinositide 3-kinase (PI3K) inhibitor), an Akt inhibitor, and stable transfection of dominant negative-Akt1. ANG II induced a significant increase in PI3K activity, which was abolished by co-treatment with losartan or 2,5-dideoxyadenosine (2,5-DOA, an adenylyl cyclase inhibitor) but not by PD123319 (an AT-2R antagonist) or H89 (a protein kinase A (PKA) inhibitor). The Epac (exchange protein directly activated by cAMP)-specific cAMP analog, 8-pHPT-2-O-MecAMP, significantly increased PI3K activity, whereas a PKAspecific analog, 6-benzoyladenosine-cAMP, showed no effect. The ANG II-induced increase in PI3K activity was also blocked by co-treatment with PP2, an Src inhibitor, or AG1478, an epidermal growth factor receptor (EGFR) antagonist. ANG II induced phosphorylation of Akt and p70S6K and EGFR, which was abrogated by knockdown of c-Src by small interference RNA. Knockdown of Src also effectively abolished ANG II-induced collagen synthesis. Conversely, stable transfection of a constitutively active Src mutant enhanced basal PI3K activity and collagen production, which was abrogated by AG1478 but not by 2,5-DOA. Moreover, acute treatment with ANG II significantly increased Src activity, which was abrogated with co-treatment of 2,5-DOA. Taken together, these results suggest that ANG II induces collagen synthesis in MCs by activating the ANG II/AT-1R-EGFR-PI3K pathway. This transactivation is dependent on cAMP/Epac but not on PKA. Src kinase plays a pivotal role in this signaling pathway between cAMP and EGFR. This is the first demonstration that an AT1R-PI3K/ Akt crosstalk, along with transactivation of EGFR, mediates ANG II-induced collagen synthesis in MCs.Clinical and experimental studies have identified the reninangiotensin system as a key factor in development and progression of glomerular diseases (1-3). A chronically enhanced effect of the renin-angiotensin system is a central event in the development of proliferative and sclerosing changes in the glomeruli. The octapeptide hormone angiotensin II (ANG II), 2 the major renin-angiotensin system effector, activates mesangial cells (MCs) and increases the synthesis of extracellular matrix components, including collagens, which is a hallmark of the glomerular diseases (4, 5). The physiological functions of ANG II are mediated by at least two structurally and pharmacologically distinct seven-transmembrane helices G protein-coupled receptors (GPCRs), ANG II type 1 and 2 receptors (AT-1R and AT-2R). Glomerular cells, including MCs, express primarily the AT-1R, ...

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Section: Discussionmentioning

confidence: 99%

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

Yano

Suzuki

Endoh

et al. 2007

Journal of Biological Chemistry

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“…11,12 The primary action of the RAS is to regulate vascular tone and renal salt excretion. However, recent data indicate that, independently of its effects on blood pressure, AII may augment the accumulation of extracellular matrix.…”

mentioning

confidence: 99%

Host genetic factors influence disease progression in chronic hepatitis C

et al. 2000

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Progressive hepatic fibrosis and cirrhosis develops in 20% to 30% of patients with chronic hepatitis C virus (HCV). We propose that host genetic factors influencing fibrogenesis may account for some of the variability in progression of this disease. In progressive fibrosis of other organs, particularly heart and kidney, production of the profibrogenic cytokine, transforming growth factor β1 (TGF‐β1), may be enhanced by angiotensin II, the principal effector molecule of the renin‐angiotensin system. The inheritance of polymorphisms in TGF‐β1, interleukin 10 (IL‐10), tumor necrosis factor α (TNF‐α), and genes of the renin‐angiotensin system was examined in 128 patients with chronic HCV. The influence of genotypes on the stage of hepatic fibrosis was tested after adjustment for potential confounders (age, gender, alcohol consumption, portal inflammation, and steatosis), which may have independent effects on histological severity. The stage of fibrosis was 0 in 30 (23.4%), 1 in 44 (34.4%), 2 in 27 (21.1%), and 3 or 4 in 27 (21.1%). A statistically significant relationship was seen between inheritance of high TGF‐β1– and angiotensinogen (AT)‐producing genotypes and the development of progressive hepatic fibrosis. This association persisted after correcting for potential confounders. Patients who inherited neither of the profibrogenic genotypes had no or only minimal fibrosis. Knowledge of these polymorphisms may have prognostic significance in patients with chronic HCV and may direct more aggressive therapy towards those patients with an increased risk of disease progression. The documentation of a significant relationship between AT genotype and fibrosis raises the novel suggestion that angiotensin II may be another mediator of extracellular matrix production in the liver.

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“…Endothelial injury is also involved in the initiation and propagation of glomerulosclerosis and ESRD (5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Protection of Endothelial Cells by Dextran Sulfate in Rats with Thrombotic Microangiopathy

Eto

Kojima

Uesugi

et al. 2005

Journal of the American Society of Nephrology

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The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury in association with loss of heparan sulfate proteoglycans on the cell surface and thrombus formation, followed by subsequent ischemic tubulointerstitial damage. It therefore was hypothesized that dextran sulfate (DXS) may protect the kidney against endothelial damage in a model of TMA. TMA was induced in rats by renal artery perfusion of an antiglomerular endothelial antibody, followed by the administration of DXS or vehicle. Renal damage was assessed by histologic analysis and measurements of blood urea nitrogen and creatinine. Whereas control rats developed severe renal failure with extensive glomerular and tubular injury, administration of DXS significantly protected renal function and preserved the glomerular endothelium and peritubular capillaries. The beneficial effect of DXS could be attributed to the ability of DXS to protect endothelial cells from coagulation and complement activation, as demonstrated by the histologic analysis. In addition, binding of the administered DXS to the surface of the glomerular endothelium was confirmed in TMA rats, suggesting that DXS acts as a "repair coat" of injured glomerular endothelium. In conclusion, DXS protects the kidney from experimental TMA. This protection may be mediated by DXS's binding directly to the surface of glomerular endothelium and amelioration of coagulation, complement activation, and cellular matrix loss.

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Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney.

Cited by 191 publications

References 47 publications

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

Host genetic factors influence disease progression in chronic hepatitis C

Protection of Endothelial Cells by Dextran Sulfate in Rats with Thrombotic Microangiopathy

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