Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In chronic diseases such as diabetes mellitus, continuous stress stimuli trigger a persistent, self-reinforcing reprogramming of cellular function and gene expression that culminates in the pathological state. Late-onset, stable changes in gene expression hold the key to understanding the molecular basis of chronic diseases. Renal failure is a common, but poorly understood complication of diabetes. Diabetic nephropathy begins with mesangial cell hypertrophy and hyperplasia, combined with excess matrix deposition. The vasoactive peptide endothelin promotes the mesangial cell hypertophy characteristic of diabetic nephropathy. In this study, we examined the signaling pathways and changes in gene expression required for endothelin-induced mesangial cell hypertrophy. Transcriptional profiling identified seven genes induced with slow kinetics by endothelin. Of these, p8, which encodes a small basic helix-loop-helix protein, was most strongly and stably induced. p8 is also induced in diabetic kidney. Mesangial cell hypertrophy and p8 induction both require activation of the ERK, JNK/SAPK and PI-3-K pathways. Small interfering RNA (siRNA)-mediated RNA interference indicates that p8 is required for endothelin-induced hypertrophy. Thus, p8 is a novel marker for diabetic renal hypertrophy.
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PMID:Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy. 1237 43

We examined the effect of PGE1 on the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA induced by tumor necrosis factor-alpha (TNF-alpha) in human mesangial cells, because PAI-1 is one of major factors for the progression of glomerulosclerosis. The expression of PAI-1 mRNA was increased after stimulation with TNF-alpha, and it was diminished by pre-incubation with PGE1. Next, we examined the effect of PGE1 on the phosphorylation of mitogen activated protein kinase (MAPK) family and Akt. TNF-alpha activated the phosphorylation of p44/42 MAPK, p38 MAPK, SAPK/JNK and Akt in mesangial cells. PGE1 inhibited the TNF-alpha induced phosphorylation of SAPK/JNK and Akt, but not p44/42 MAPK and p38 MAPK. The TNF-alpha induced expression of PAI-1 mRNA was not affected by PD98059, an inhibitor of MEK, SB203580, an inhibitor of p38 MAPK, nor LY294002, an inhibitor of PI3 K. However, DMAP, an inhibitor of SAPK/JNK, inhibited the expression of PAI-1 mRNA, suggesting that the TNF-alpha induced expression of PAI-1 mRNA is regulated by the SAPK/JNK dependent pathway in human mesangial cells. By the incubation with H8, an inhibitor of PKA, the inhibitory effect of PGE1 on the expression of PAI-1 mRNA was abolished, suggesting that PGE1 inhibited the PAI-1 mRNA expression via the PKA pathway. Our results suggest that the inhibition of PAI-1 synthesis by PGE1 in human mesangial cells may have therapeutic implications for glomerulosclerosis such as occurs in diabetic nephropathy.
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PMID:PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells. 1602 96

Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis under chronic pathological conditions, including DN (diabetic nephropathy). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins. CTGF (connective tissue growth factor) is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to HMCs (human mesangial cells) rapidly activates ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6 (MAPK kinase 3/6). The aim of the present study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMCs. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MKP-1 (MAPK phosphatase-1), a dual specificity phosphatase that dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, Bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA (small interfering RNA) or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.
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PMID:Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1). 1748 38

Chronic inflammation and increased oxidative stress (OS) play an important role in diabetic nephropathy progression. Herein, we show that mesangial cells from streptozotocin-induced aging diabetic mice, a model of progressive diabetic nephropathy, exhibited increased OS and a proinflammatory phenotype characterized by elevated chemokines and ICAM-1 expression. This phenotypic change was consistent with the extensive inflammatory lesions present in aging diabetic kidneys and was not found in mesangial cells from old and young controls or young diabetic mice. Activation of the c-Jun NH(2)-terminal kinase (JNK) pathway was a likely contributor to the proinflammatory phenotype of aging diabetic mesangial cells since 1) phosphorylated JNK levels and JNK kinase activity were increased in these cells, 2) suppression of JNK significantly decreased monocyte chemoattractant protein-1 (MCP-1) production in these cells, and 3) activation of JNK in normal mesangial cells induced inflammation. Elevated OS in aging diabetic mesangial cells may be a cause of JNK activation and inflammation, because antioxidant treatment decreased JNK phosphorylation and MCP-1 production. Additionally, decreased expression of mitogen-activated protein kinase phosphatase 5 (MKP5) may also contribute to increased JNK and inflammation in aging diabetic mesangial cells since overexpression of MKP5 in these cells normalized phosphorylated JNK levels and reversed the proinflammatory phenotype. Moreover, knocking down of MKP5 expression in old control mesangial cells resulted in JNK activation and MCP-1 production, a phenotype seen in aging diabetic mesangial cells. Interestingly, MKP5 phosphatase activity was diminished by free radicals in vitro. Thus, OS may induce inflammation in mesangial cells by activating JNK through either a direct activation of JNK or indirectly by suppression of MKP5 activity. Proinflammatory phenotype of mesangial cells may contribute to chronic inflammatory lesions and disease progression of aging diabetic mice.
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PMID:Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells. 1977 74

Aldose reductase (AR) has emerged as a key contributor to the diabetic nephropathy (DN), however, the mechanisms by which AR increases DN remain poorly understood. Here, we report that exposure to high glucose (HG) stimulates fibronectin (FN) from human mesangial cells in culture. Our results show that exposure to HG and overexpression AR increase the expression of FN. This increase was prevented by the AR inhibitors sorbinil and zopolrestat. Treatment with HG and transfected with plasmid PcDNA3.0-AR, resulted in phosphorylation and activation of ERK, JNK and AKT signaling pathway, and increase the expression of FN. Treatment with inhibitor of JNK and AKT signaling pathway decreased the expression of FN. These results show that inhibition of AR may be useful to prevented extracellular matrix (ECM) deposition in diabetic nephropathy, which is regulated by JNK and AKT.
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PMID:Role of aldose reductase in the high glucose induced expression of fibronectin in human mesangial cells. 1982 Oct 53

The profibrotic adhesion molecule, osteopontin (OPN), is upregulated in kidneys of humans and mice with diabetes. The thiazolidinedione (TZD) insulin sensitizers decrease albuminuria in diabetic nephropathy (DN) and reduce OPN expression in vascular and cardiac tissue. To examine whether OPN is a critical mediator of DN we treated db/db mice with insulin, rosiglitazone, or pioglitazone to achieve similar fasting plasma glucose levels. The urine albumin-to-creatinine ratio and glomerular OPN expression were increased in diabetic mice, but both were reduced by the TZDs more than by insulin. We administered streptozotocin to OPN-null and OPN-wild-type mice, and OPN-null mice were bred into both type 1 (Ins2(akita/+)) and 2 (db/db) diabetic mice. In each case, OPN deletion decreased albuminuria, mesangial area, and glomerular collagen IV, fibronectin and transforming growth factor (TGF)-beta in the diabetic mice compared with their respective controls. In cultured mouse mesangial cells, TZDs but not insulin decreased angiotensin II-induced OPN expression, while recombinant OPN upregulated TGF-beta, ERK/MAPK, and JNK/MAPK signaling. These studies show that OPN expression in DN mouse models enhances glomerular damage, likely through the expression of TGF-beta, while its deletion protects against disease progression, suggesting that OPN might serve as a therapeutic target.
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PMID:Critical role for osteopontin in diabetic nephropathy. 2022 82

A lot of anti-diabetic agents using natural plants have been extensively studied. Ginsenosides are known to be used as a remedy for diabetes in Asian countries and American Societies. Diabetic nephropathy is a major complication of diabetes mellitus. Extracellular matrix in mesangial cells is mainly composed of fibronectin and the increase of fibronectin is a hallmark of diabetic nephropathy. Protopenaxadiol (PPD) is a major component of total ginseng. Thus, we examined the regulatory mechanism of PPD derivatives-induced preventive effect of fibronectin expression in mesangial cells cultivated under diabetic condition. In present study, ginsenoside Rb1 prevented the high glucose-induced increase of fibronectin expression in mesangial cells. Ginsenoside Rb2 and Rg3 also mildly inhibited it. However, ginsenoside Rc and Rd did not prevent the high glucose-induced increase of fibronectin expression in mesangial cells. In addition, ginsenoside Rb1 prevented high glucose-induced phosphorylation of p44/42 mitogen activated protein kinase (MAPK), p38 MAPK, JNK/SAPK, and Akt. These results suggest that ginsenoside Rb1 is the most powerful component of PPD derivatives. In conclusion, ginsenoside Rb1 prevented high glucose-induced increase of fibronectin expression via the inhibition of MAPK-Akt signaling cascade.
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PMID:Effect of protopanaxadiol derivatives in high glucose-induced fibronectin expression in primary cultured rat mesangial cells: role of mitogen-activated protein kinases and Akt. 2019 56

TNF-alpha has recently been implicated in diabetic nephropathy, which is usually accompanied by higher sodium retention. The kidneys play a major role in sodium homeostasis by regulating tubular sodium reabsorption, a process geared by the sodium gradient established by the Na(+)/K(+) ATPase. The aim of this work was to investigate the effect of TNF on the ATPase, and consequently its implication in kidney malfunction, using LLC-PK1 cells. The cytokine reduced the Na(+)/K(+)ATPase activity significantly. In an attempt to elucidate the signalling pathway involved, PDTC (pyrrolidinedithiocarbamate), SP600125 and FK009 respectively inhibitors of NF-kappaB, c-JNK and caspases, were added to the cells in the presence and absence of TNF, and changes in the activities of JNK and PDTC were determined. The activity of the pump was assayed by measuring the ouabain-inhibitable release of inorganic phosphate. The effect of the cytokine was abrogated completely when JNK and caspases were inhibited but was unaffected by NF-kappaB inhibition. The role of each mediator in the signalling cascade was studied further by applying different combinations of the inhibitors. TNF-alpha was found to act at 1 h by activating caspases, which in turn activate JNK; the latter exerts an inhibitory effect on NF-kappaB, a transcription factor that stimulates the Na(+)/K(+) ATPase when active. It was concluded that TNF-alpha exerts opposite effects on the Na(+)/K(+)ATPase at different times, though the effects are always mediated via cJNK, NF-kappaB and caspases.
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PMID:TNF-alpha reduces the Na+/K+ ATPase activity in LLC-PK1 cells by activating caspases and JNK and inhibiting NF-kappaB. 2022 69

Elevated glomerular capillary pressure (Pgc) and hyperglycemia contribute to glomerular filtration barrier injury observed in diabetic nephropathy (DN). Previous studies showed that hypertensive conditions alone or in combination with a diabetic milieu impact podocyte cellular function which results in podocyte death, detachment or hypertrophy. The present study was aimed at uncovering the initial signaling profile activated by Pgc (mimicked by in vitro mechanical stretch), hyperglycemia (high glucose (HG), 25mM d-glucose) and prostaglandin E(2) (PGE(2)) in conditionally-immortalized mouse podocytes. PGE(2) significantly reduced the active form of AKT by selectively blunting its phosphorylation on S473, but not on T308. AKT inhibition by PGE(2) was reversed following either siRNA-mediated EP(4) knockdown, PKA inhibition (H89), or phosphatase inhibition (orthovanadate). Podocytes treated for 20min with H(2)O(2) (10(-4)M), which mimics reactive oxygen species generation by cells challenged by hyperglycemic or enhanced Pgc conditions, significantly increased the levels of active p38 MAPK, AKT, JNK and ERK1/2. Interestingly, stretch and PGE(2) each significantly reduced H(2)O(2)-mediated AKT phosphorylation and was reversed by pretreatment with orthovanadate while stretch alone reduced GSK-3beta inhibitory phosphorylation at ser-9. Finally, mechanical stretch alone or in combination with HG, induced ERK1/2 and JNK activation, via the EGF receptor since AG1478, a specific EGF receptor kinase inhibitor, blocked this activation. These results show that cellular signaling in podocytes is significantly altered under diabetic conditions (i.e., hyperglycemia and increased Pgc). These changes in MAPKs and AKT activities might impact cellular integrity required for a functional glomerular filtration barrier thereby contributing to the onset of proteinuria in DN.
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PMID:Mechanical stretch and prostaglandin E2 modulate critical signaling pathways in mouse podocytes. 2036 52

The present study sought to investigate the effects of ursolic acid (UA) on the development of glomerular hypertrophy and type IV collagen accumulation, two early lesions associated with diabetic nephropathy (DN). By treating streptozotocin (STZ)-induced diabetic mice with low-dose UA (0.01% in food) for three months, the diabetes-induced glomerular hypertrophy and type IV collagen accumulation in the kidneys were found to be markedly ameliorated. Further studies identified that UA treatment suppressed diabetes-induced activations of STAT-3, ERK1/2 and JNK pathways, but not the diabetes-induced activation of the p38 pathway. Furthermore, diabetes-induced overexpression of iNOS in the renal cortex was also significantly suppressed by the treatment. UA may thus be considered as a potential therapeutic agent in treating DN.
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PMID:Ursolic acid inhibits early lesions of diabetic nephropathy. 2081 97


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