Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice

Menne, Jan; Park, Joon-Keun; Boehne, Martin; Elger, Marlies; Lindschau, Carsten; Kirsch, Torsten; Meier, Matthias; Gueler, Faikah; Fiebeler, Annette; Bahlmann, Ferdinand H.; Leitges, Michael; Haller, Hermann

doi:10.2337/diabetes.53.8.2101

Cited by 126 publications

(144 citation statements)

References 55 publications

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“…Diabetic PKC-␣ knockout mice had comparable upregulation of glomerular TGF-␤ as their wild-type counterparts, whereas TGF-␤ upregulation was abrogated in diabetic PKC-␤ knockouts. 10,11,41 The TGF-␤1 promoter has regulatory binding sites for the transcription factor AP-1. 13 AP-1 is activated by HG in MCs and in diabetic kidneys.…”

Section: Discussionmentioning

confidence: 99%

“…PI3K/Akt signaling mediated glucose-induced hypertrophy in MC and tubular epithelia. 15,48 Glomerular hypertrophy is attenuated in diabetic PKC-␤ null mice, 10,11 whereas PKC␣ deletion did not affect this parameter, 41 thus supporting a role for PKC-␤1/Akt signaling in mediating cell and organ size. Although a significant decrease in renal hypertrophy was not observed in type 1 diabetic rats treated with ruboxistaurin, glomerular hypertrophy was not specifically assessed.…”

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

confidence: 99%

“…For example, PKC␣ translocation is preserved in diabetic PKC-␤ knockout mice, and, indeed, albuminuria in the PKC␣ knockout phenotype is prevented, with no significant changes observed in PKC-␤ knockouts. 10,41 Because PDK1 and PI3K would also be expected to be upstream of other isoforms, including PKC␣, 23 targeting these effectors may lead to greater improvement in renal protection. In vivo studies would be required to assess this possibility, given the potential of adverse effects from inhibition of other downstream targets.…”

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

confidence: 99%

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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

102

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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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Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

See 1 more Smart Citation

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

102

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“…Other pathways in addition to PKC-␤ may also mediate some of these processes. Recently, it was shown that hyperglycemia-induced downregulation of the negatively charged basement membrane heparin sulfate proteoglycan perlecan was prevented in mice lacking PKC-␣, which also had a reduction in diabetes-associated albuminuria (44). Our data on PKC activity in renal cortex and activation of the ␣ isoform in the PKC-␤ Ϫ/Ϫ mice would be consistent with the view that activation of PKC-␣ may also contribute to albuminuria observed in diabetes despite it not being involved in causing extracellular matrix accumulation and renal hypertrophy.…”

Section: Diabetes Vol 55 November 2006mentioning

confidence: 99%

Reduction of Diabetes-Induced Oxidative Stress, Fibrotic Cytokine Expression, and Renal Dysfunction in Protein Kinase Cβ–Null Mice

et al. 2006

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“…Genetic studies in the mouse have indicated that particular PKC isoforms are essential in a number of specific contexts [67][68][69][70][71][72][73][74][75]. As would be expected given their multiple and specific properties in vitro, the deletion of individual PKC isoform pathways leads to distinct phenotypes in KO mice [28,[76][77][78][79]. Surprisingly, in a given cascade, KOs of the various isoforms assign specific non-redundant biological functions to each isoform, which were not compensated for by the others [28,[76][77][78][79].…”

Section: Retinopathy the Overall Results For Two Studies Of Diabetic Rmentioning

confidence: 99%

Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice

2009

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The protein kinase C (PKC) superfamily comprises proteins that are activated in response to various pathogenic stimuli in the diabetic state. Hyperglycaemia is the predominant stimulus that induces the activation of distinct PKC isoforms within a cell, each mediating specific functions, probably through differential subcellular localisation. The contribution of individual PKC isoforms can be directly addressed in vivo using innovative PKC-isoformspecific knockout (KO) mouse models, which are providing key insights into the physiological function of PKC isoform diversity in the development of diabetic nephropathy. Such studies can be a valuable complementary approach to more commonly used pharmacological analyses using agents such as ruboxistaurin mesylate (Arxxant, LY333531), which is claimed to specifically inhibit the PKC-β-isoform. As expected given the multiple and specific properties of the isoforms in vitro, deletion of different PKC isoform signalling pathways leads to distinct phenotypes in mice. Notably, KOs of the individual PKCs assigned specific non-redundant biological functions to each isoform, which were not compensated for by the others. Thus, PKC isoform specificity and cellular diversity seem to be responsible for the divergent outcomes leading to albuminuria and/or renal fibrosis according to studies on the streptozotocin-induced mouse model of diabetes. This review discusses the role of individual PKC isoforms in diabetic nephropathy and their potential therapeutic implications. Defining and targeting mediators of increased intracellular activation in the diabetic microvasculature will have important clinical and therapeutic benefits and help in the design of novel effective therapies in the near future.

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Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice

Cited by 126 publications

References 55 publications

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

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

Reduction of Diabetes-Induced Oxidative Stress, Fibrotic Cytokine Expression, and Renal Dysfunction in Protein Kinase Cβ–Null Mice

Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice

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