Protein kinase C β inhibition: the promise for treatment of diabetic nephropathy

Anderson, Pamela W.; McGill, Janet B.

doi:10.1097/mnh.0b013e3281ead025

Cited by 20 publications

(14 citation statements)

References 33 publications

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“…In vivo, both PKC␤ inhibition and genetic deletion suppressed TGF-␤1 upregulation and matrix expansion in diabetic glomeruli or kidneys (2,31). Using a PKC␤-specific inhibitor and PKC␤1 siRNA, our data are the first to show that PKC␤ is an important mediator of RhoA activation.…”

Section: F166 Caveolae Mediate Ros Generation In High Glucosementioning

confidence: 72%

“…Although PKC comprises a large family of kinases, the best established upstream activator of RhoA is PKC␣ (16,18). The importance of conventional isoforms PKC␣ and -␤ to the pathogenesis of diabetic nephropathy was demonstrated through the study of knockout mice and use of a PKC␤ inhibitor (2,31,32). However, PKC␤ has not as yet been implicated in RhoA activation.…”

mentioning

confidence: 99%

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High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

Zhang

Peng

Gao

et al. 2012

American Journal of Physiology-Renal Physiology

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Section: F166 Caveolae Mediate Ros Generation In High Glucosementioning

confidence: 72%

mentioning

confidence: 99%

High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

Zhang

Peng

Gao

et al. 2012

American Journal of Physiology-Renal Physiology

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“…29 Ruboxistaurin prevents ATP binding to the active site of PKC-␤, thereby inhibiting its ability to phosphorylate substrates and functioning as a specific PKC-␤ inhibitor. 30 It was shown to decrease glomerular TGF-␤ upregulation, glomerulosclerosis, and albuminuria in this model. 31 After 12 wk, there was no difference between groups in systolic BP (control 204 Ϯ 14 mmHg, STZ 208 Ϯ 10 mmHg, STZϩRub 218 Ϯ 7 mmHg).…”

Section: Pkc-␤ Inhibition In Vivo Prevents Akt S473 Phosphorylation Imentioning

confidence: 99%

“…Both PKC-␤ inhibition and PKC-␤ deletion suppressed TGF-␤1 upregulation and matrix expansion in diabetic glomeruli or kidneys. 10,11,30 We previously showed pAktS473 in diabetic glomeruli. 1 We now demonstrate that PKC-␤ inhibition with ruboxistaurin prevents Akt phosphorylation in diabetic kidneys, supporting a function for PKC-␤/Akt in the TGF-␤ upregulation identified in our in vitro studies.…”

Section: Hg Versus Others) (D) Ap-1 Activity Was Also Prevented Inmentioning

confidence: 99%

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Peng²,

Zhang³

et al. 2009

Journal of the American Society of Nephrology

105

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Accumulation of glomerular matrix is a hallmark of diabetic nephropathy. The serine/threonine kinase Akt mediates glucose-induced upregulation of collagen I in mesangial cells through transactivation of the EGF receptor (EGFR). In addition, in renal tubular cells, glucose-induced secretion of TGF-␤ requires phosphoinositide-3-OH kinase, suggesting a possible role for Akt in the modulation of TGF-␤ expression, but the mechanisms of Akt activation and its involvement in TGF-␤ regulation are unknown. Here, in primary mesangial cells, high glucose induced AktS473 phosphorylation, which correlates with its activation, in a protein kinase C ␤ (PKC-␤)-dependent manner. Glucose led to PKC-␤1 membrane translocation and association with Akt, and PKC-␤1 immunoprecipitated from glucose-treated cells phosphorylated recombinant Akt on S473. PKC is known to mediate glucose-induced TGF-␤1 upregulation through the transcription factor AP-1; here, inhibitors of phosphoinositide-3-OH kinase, PKC-␤ and Akt, and dominant-negative Akt all prevented glucose-induced activation of AP-1 and upregulation of TGF-␤1. Finally, pharmacologic and dominant negative inhibition of EGFR blocked glucose-induced activation of PKC-␤1, phosphorylation of AktS473, activation of AP-1, and upregulation of TGF-␤1. In vivo, the PKC-␤ inhibitor ruboxistaurin prevented Akt activation in the renal cortex of diabetic rats. In conclusion, PKC-␤1 is an Akt S473 kinase in glucose-treated mesangial cells, and TGF-␤1 transcriptional upregulation requires EGFR/PKC-␤1/Akt signaling. New therapeutic approaches for diabetic nephropathy may result from targeting components of this pathway, particularly the initial EGFR transactivation. 20: 554 -566, 200920: 554 -566, . doi: 10.1681 The kidney is an important site of diabetic microvascular complications, and hyperglycemia is central to glomerular matrix accumulation. Although strict glucose control and inhibition of the reninangiotensin system are effective in delaying the development of nephropathy, disease progression often occurs. The development of new treatment approaches is thus an important goal. J Am Soc NephrolWe have shown that collagen I induction by high glucose (HG) requires activation of the serine/threonine kinase Akt, and this depends on transactivation of the EGF receptor (EGFR). 1 Akt activation requires membrane translocation and phosphorylation on two sites, S473 and T308. 2 Phosphoinositide-3-OH kinase (PI3K) is an upstream mediator of Akt activation, generating phosphorylated lipid second messengers that recruit proteins with pleckstrin homology domains such as Akt to the membrane. 3 At the membrane, phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates Akt at T308. 3 Several S473 kinases, however, have

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“…The discovery of the simplest bisindolylmaleimide natural product, arcyriarubin A, [2] from a slime mold ( Arcyria denudate ) spearheaded the extensive study of this class of compounds, with more than 2,400 and 4,000 bisindolylmaleimide-related references in the PubMed and SciFinder databases, respectively. Bisindolylmaleimide analogs, with activities in cancer, [3] diabetes, [4] cardiovascular [5] and neurodegenerative [6] disease models have now been synthesized, some of which have advanced into clinical trials [7] (Scheme 1A). Surprisingly, bisindolylmaleimide biosynthesis has remained uncharacterized.…”

mentioning

confidence: 99%

Characterization of an Environmental DNA‐Derived Gene Cluster that Encodes the Bisindolylmaleimide Methylarcyriarubin

Chang¹

2014

ChemBioChem

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Bisindolylmaleimides represent a naturally occurring class of metabolites that are of interest because of their protein kinase inhibition activity. From a metagenomic library constructed using soil DNA, we identified the four gene mar cluster, a bisindolylmaleimide gene cluster that encodes for methylarcyriarubin (1) production. Heterologous expression of the mar gene cluster in Escherichia coli revealed that the Rieske dioxygenase, MarC, facilitates the oxidative decarboxylation of a chromopyrrolic acid (CPA) intermediate to yield the bisindolylmaleimide core. The characterization of the mar cluster defines a new role for CPA in the biosynthesis of structurally diverse bacterial tryptophan dimers.

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Protein kinase C β inhibition: the promise for treatment of diabetic nephropathy

Abstract: Inhibition of protein kinase C beta may represent a novel strategy to improve kidney outcomes in patients with diabetes mellitus. Large-scale, prospective trials are needed to confirm the safety and potential benefits of ruboxistaurin in patients with diabetic nephropathy.

Cited by 20 publications

References 33 publications

High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Characterization of an Environmental DNA‐Derived Gene Cluster that Encodes the Bisindolylmaleimide Methylarcyriarubin

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