UMLS:C0011881 - FACTA Search

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Query: UMLS:C0011881 (diabetic nephropathy)
10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced glycation end product (AGE) is important in the pathogenesis of diabetic nephropathy, which is characterized by cellular hypertrophy/hyperplasia leading to renal fibrosis. However, the signal transduction pathways of AGE remain poorly understood. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway has been associated with cellular proliferation in some extra-renal cells. Because interstitial fibroblast proliferation might be important in renal fibrosis, we studied the role of the JAK/STAT pathway in NRK-49F (normal rat kidney fibroblast) cells cultured in AGE/BSA and non-glycated BSA. We showed that AGE dose-dependently (10-200 microgram/ml) increased cellular mitogenesis in NRK-49F cells at 5 and 7 days. However, cellular mitogenesis was unaffected by the simultaneous presence of BSA. Regarding the JAK/STAT pathway, AGE (100 microgram/ml) induced tyrosine phosphorylation of JAK2 (but not JAK1, JAK3 or TYK2) at 15-60 min; it also induced the tyrosine phosphorylation of STAT1 and STAT3 at 1-2 h and 0.5-4 h respectively. Being a transcription factor, AGE also increased the DNA-binding activities of STAT1 and STAT3 AG-490 (a specific JAK2 inhibitor) (5 microM) inhibited tyrosine phosphorylation of JAK2 and the DNA-binding activities of STAT1 and STAT3. The same results were obtained by using specific 'decoy' oligodeoxynucleotides (ODNs) that prevented STAT1 and STAT3 from binding to DNA. Meanwhile, the STAT1 or STAT3 decoy ODN and AG-490 were effective in reversing AGE-induced cellular mitogenesis. We concluded that the JAK2-STAT1/STAT3 signal transduction pathway is necessary for AGE-induced cellular mitogenesis in NRK-49F cells.
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PMID:Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells. 1043 21

Glomerular proteinuria is a risk factor for progression of chronic renal failure and contributes to renal interstitial fibrosis. In experimental diabetic glomerular sclerosis, there is translocation of high-molecular-weight growth factors, namely, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta, from plasma into tubular fluid, both of which act on tubular cells through apical membrane receptors. In the present studies, the hypothesis is examined that ultrafiltered HGF and TGF-beta induce increased expression of extracellular matrix (ECM) proteins directly in tubular cells, or induce increased expression of cytokines that may act on interstitial myofibroblasts. Incubation of cultured tubular cells with recombinant human (rh) TGF-beta modestly raises expression of collagen type III, but rhHGF dose dependently blocks expression of this ECM protein. Both growth factors raise fibronectin expression up to fourfold and increase expression of platelet-derived growth factor (PDGF)-BB up to sixfold, but not of fibroblast growth factor-2. Pooled, diluted glomerular ultrafiltrate that had been collected by nephron micropuncture from rats with diabetic nephropathy (24-30 wk) also raises expression of fibronectin as well as PDGF-BB in proximal tubular cells. In the presence of neutralizing antibodies that block actions of HGF and TGF-beta, diabetic rat glomerular ultrafiltrate fails to increase tubular cell PDGF-BB expression. In NRK-49F renal interstitial myofibroblasts, rhPDGF-BB, in turn, raises the expression of collagen type III but not type I or fibronectin. The findings provide evidence for ultrafiltered HGF and TGF-beta to contribute to interstitial accumulation of ECM proteins by direct effects on tubular cells as well as indirect mechanisms, via PDGF-BB and its action on myofibroblasts. These events may be important mechanisms of proteinuria-induced renal interstitial fibrosis and accelerated progression of chronic renal failure in diabetic nephropathy and perhaps other proteinuric glomerular diseases.
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PMID:Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis. 1075 Dec 15

Advanced glycation end-product (AGE) is important in the pathogenesis of diabetic nephropathy (DN), and captopril (an angiotensin converting enzyme inhibitor) is effective in treating this disorder. We have shown that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade is responsible for AGE-induced mitogenesis in NRK-49F (normal rat kidney fibroblast) cells, but its role in renal fibrosis in DN remains unknown. Therefore, we have sought to determine whether JAK/STAT is involved in AGE-regulated collagen production in NRK-49F cells. We found that AGE time (1-7 days) and dose (10-200 microg/ml)-dependently increased collagen production in these cells. Additionally, AGE increased RAGE (receptor for AGE) protein expression. AGE-induced RAGE expression was dose-dependently inhibited by antisense RAGE oligodeoxynucleotide (ODN) and captopril. AGE-induced type I collagen production and JAK2-STAT1/STAT3 activation were decreased by AG-490 (a specific JAK2 inhibitor), antisense RAGE ODN and captopril. Meanwhile, STAT1 and STAT3 decoy ODNs also suppressed the induction of collagen by AGE. We concluded that RAGE and the JAK2-STAT1/STAT3 pathway were involved in AGE-induced collagen production in NRK-49F cells. Furthermore, captopril was found to reverse AGE-induced collagen production, probably by attenuating RAGE expression and JAK2-STAT1/STAT3 activities.
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PMID:Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. 1118 Apr 1

Advanced glycation end products (AGEs) are important in the pathogenesis of diabetic nephropathy, which leads to renal fibrosis. Previously, we found that the janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway is necessary for AGE-induced cellular proliferation in normal rat kidney interstitial fibroblast (NRK-49F) cells. However, a direct link between JAK/STAT and cell-cycle progression has not been well established. In this regard, STAT5 has been found to induce cyclin D1 and proliferation in hematopoietic cells. Therefore, we examined effects of AGE on STAT5 and cell-cycle-dependent mitogenesis in NRK-49F cells. We found that AGE increased cyclin D1 expression and cyclin-dependent kinase (cdk)4 activity while decreasing p21(WAF1/CIP1) expression. We also found that AGE (100 microg/mL) induced STAT5 tyrosine phosphorylation. Meanwhile, AGE induced STAT5 protein-DNA binding activity, which was reversed by AG-490 (a specific JAK2 inhibitor) and STAT5 decoy oligodeoxynucleotide (ODN). In addition, STAT5 decoy ODN reversed AGE-induced cell-cycle-dependent cellular proliferation and cyclin D1 protein expression. We concluded that AGE induced cell-cycle-dependent cellular proliferation by inducing the JAK2-STAT5-cyclin D1 and cdk4 pathways in NRK-49F cells.
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PMID:Advanced glycation end product-induced proliferation in NRK-49F cells is dependent on the JAK2/STAT5 pathway and cyclin D1. 1168 65

High-protein diets exacerbate glomerular hyperfiltration and the progression of diabetic nephropathy. The purpose of this study was to determine whether amino acids also produce nonhemodynamic injury in the glomerulus. When rat mesangial cells were cultured with an amino acid mixture designed to replicate the composition in plasma after protein feeding, production of mRNA (Northern blot analysis) and/or protein (ELISA or Western blot analysis) for transforming growth factor-beta1 (TGF-beta1), fibronectin, thrombospondin-1 (TSP-1), and collagen IV were enhanced in a manner comparable to a culture with high glucose (30.5 mM). The bioactive portion of total TGF-beta (NRK assay) increased in response to amino acids. The TSP-1 antagonist LSKL peptide reduced bioactive TGF-beta and fibronectin, indicating the dependence of TGF-beta1 activation on TSP-1. DNA synthesis ([3H]thymidine incorporation), an index of cellular proliferation, increased in response to amino acids and was further enhanced by culture with increased levels of both amino acids and glucose. TGF-beta1 and matrix proteins increased when mesangial cells were cultured with excess l-arginine (2.08 mM) alone. Although l-arginine is the precursor of nitric oxide (NO), such responses to amino acids do not appear to be mediated through increased NO production. NO metabolites decreased in the media, and these responses to mixed amino acids or l-arginine were not prevented by NO synthase inhibition. In conclusion, amino acids induce indicators of response to injury in mesangial cells, even when hemodynamic stress is absent. In conditions associated with increased circulating amino acids, such as diabetes and/or a high-protein diet, direct cellular effects could contribute to glomerular injury.
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PMID:Amino acids induce indicators of response to injury in glomerular mesangial cells. 1264 43

Diabetic nephropathy (DN) is characterized by glomerulopathy and tubulointerstitial expansion followed by renal fibrosis. Angiotensin II (Ang II) and connective tissue growth factor (CTGF) are involved in the pathogenesis of DN, while Janus kinase 2 (JAK2) is important in advanced glycation end-product (AGE)-induced effects in renal interstitial (NRK-49F) fibroblasts. Thus, we studied the role of Ang II, CTGF, and JAK2 in AGE-induced effects in NRK-49F cells. We found that AGE (150 microg/ml) increased mitogenesis and type I collagen production at 7 days while Ang II (10(-7)M) increased mitogenesis and type I collagen production at 3 days. We also found that AGE (150 microg/ml) increased angiotensinogen protein at 2 days, which was attenuated by AG-490 (a JAK2 inhibitor). AGE (150 microg/ml) increased CTGF mRNA and protein expression at 3 and 5 days, respectively. Ang II (10(-7)M) increased CTGF mRNA and protein expression at 1 and 2 days, respectively, which were attenuated by AG-490. Moreover, losartan (a type I angiotensin receptor blocker) and captopril (an angiotensin converting enzyme inhibitor) attenuated AGE-induced CTGF mRNA/protein expression while attenuating AGE-induced mitogenesis and type I collagen production. AG-490 and CTGF antisense (but not sense) oligodeoxynucleotide (ODN) attenuated Ang II (10(-7)M) and AGE-induced mitogenesis and type I collagen production at 3 and 7 days, respectively. We concluded that AGE (150 microg/ml)-induced mitogenesis and type I collagen production are dependent on the Ang II-JAK2-CTGF pathway in NRK-49F cells. Moreover, Ang II-induced mitogenesis and type I collagen production are dependent on the JAK2-CTGF pathway.
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PMID:Advanced glycation end-product-induced mitogenesis and collagen production are dependent on angiotensin II and connective tissue growth factor in NRK-49F cells. 1577 Jun 49

Renal interstitial fibrosis is believed to play a key role in the development of diabetic nephropathy (DN), and advanced glycation end-products (AGE) may contribute importantly to this. Recent reports have shown that nitric oxide (NO) is closely linked to the renal interstitial fibrosis of DN. In this study, the mechanisms by which NO and its downstream signals mediate the AGE-induced proliferative response in normal rat kidney fibroblasts (NRK-49F) are examined. AGE decreased NO production, cyclic guanosine 5'monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation time- and dose-dependently. These effects were not observed when cells were treated with nonglycated BSA. NO and inducible nitric oxide synthase (iNOS) stimulated by NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and PKG activator 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) prevented both AGE-induced proliferation and Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) activation but not p42/p44 mitogen-activated protein kinase (MAPK) activation. The ability of NO-PKG to inhibit AGE-induced cell cycle progression was verified by the observation that SNAP, SNP, and 8-pCPT-cGMP inhibited both cyclin D1 and cdk4 activation. Furthermore, induction of NO-PKG significantly increased p21Waf1/Cip1 expression in AGE-treated NRK-49F cells. The data suggest that the NO-PKG pathway inhibits AGE-induced proliferation by suppressing activation of JAK2-STAT5 and cyclin D1/cdk4 and induction of p21Waf1/Cip1.
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PMID:Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product-induced proliferation in renal fibroblasts. 1595 24

Although most cellular glutathione (GSH) is in the cytoplasm, a distinctly regulated pool is present in mitochondria. Inasmuch as GSH synthesis is primarily restricted to the cytoplasm, the mitochondrial pool must derive from transport of cytoplasmic GSH across the mitochondrial inner membrane. Early studies in liver mitochondria primarily focused on the relationship between GSH status and membrane permeability and energetics. Because GSH is an anion at physiological pH, this suggested that some of the organic anion carriers present in the inner membrane could function in GSH transport. Indeed, studies by Lash and colleagues in isolated mitochondria from rat kidney showed that most of the transport (>80%) in that tissue could be accounted for by function of the dicarboxylate carrier (DIC, Slc25a10) and the oxoglutarate carrier (OGC, Slc25a11), which mediate electroneutral exchange of dicarboxylates for inorganic phosphate and 2-oxoglutarate for other dicarboxylates, respectively. The identity and function of specific carrier proteins in other tissues is less certain, although the OGC is expressed in heart, liver, and brain and the DIC is expressed in liver and kidney. An additional carrier that transports 2-oxoglutarate, the oxodicarboxylate or oxoadipate carrier (ODC; Slc25a21), has been described in rat and human liver and its expression has a wide tissue distribution, although its potential function in GSH transport has not been investigated. Overexpression of the cDNA for the DIC and OGC in a renal proximal tubule-derived cell line, NRK-52E cells, showed that enhanced carrier expression and activity protects against oxidative stress and chemically induced apoptosis. This has implications for development of novel therapeutic approaches for treatment of human diseases and pathological states. Several conditions, such as alcoholic liver disease, cirrhosis or other chronic biliary obstructive diseases, and diabetic nephropathy, are associated with depletion or oxidation of the mitochondrial GSH pool in liver or kidney.
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PMID:Mitochondrial glutathione transport: physiological, pathological and toxicological implications. 1660 Jan 97

Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-beta1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of alpha-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-beta1 antibodies, suggesting that this action was TGF-beta1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 microM) or TGF-beta1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-beta1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-beta1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.
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PMID:Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. 1691 37

TGF-beta is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-beta to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-beta superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-beta1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-beta1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-beta receptors (TGF-beta RI). Moreover, BMP-2 significantly shortened the half-life of TGF-beta RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-beta RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-beta RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-beta. We demonstrated that BMP-2 significantly reversed the TGF-beta1-induced increase in pSmad2/3 and reversed the TGF-beta1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-beta RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson's trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-beta RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-beta RI and Smads.
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PMID:Bone morphogenetic protein-2 antagonizes renal interstitial fibrosis by promoting catabolism of type I transforming growth factor-beta receptors. 1883 4

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