scholarly journals cGMP-dependent protein kinase-2 regulates bone mass and prevents diabetic bone loss

2018 ◽  
Vol 238 (3) ◽  
pp. 203-219 ◽  
Author(s):  
Ghania Ramdani ◽  
Nadine Schall ◽  
Hema Kalyanaraman ◽  
Nisreen Wahwah ◽  
Sahar Moheize ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Bone Loss ◽  
Bone Formation ◽  
Transgenic Mice ◽  
Bone Mass ◽  
Related Gene ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

NO/cGMP signaling is important for bone remodeling in response to mechanical and hormonal stimuli, but the downstream mediator(s) regulating skeletal homeostasis are incompletely defined. We generated transgenic mice expressing a partly-activated, mutant cGMP-dependent protein kinase type 2 (PKG2R242Q) under control of the osteoblast-specific Col1a1 promoter to characterize the role of PKG2 in post-natal bone formation. Primary osteoblasts from these mice showed a two- to three-fold increase in basal and total PKG2 activity; they proliferated faster and were resistant to apoptosis compared to cells from WT mice. Male Col1a1-Prkg2 R242Q transgenic mice had increased osteoblast numbers, bone formation rates and Wnt/β-catenin-related gene expression in bone and a higher trabecular bone mass compared to their WT littermates. Streptozotocin-induced type 1 diabetes suppressed bone formation and caused rapid bone loss in WT mice, but male transgenic mice were protected from these effects. Surprisingly, we found no significant difference in bone micro-architecture or Wnt/β-catenin-related gene expression between female WT and transgenic mice; female mice of both genotypes showed higher systemic and osteoblastic NO/cGMP generation compared to their male counterparts, and a higher level of endogenous PKG2 activity may be responsible for masking effects of the PKG2R242Q transgene in females. Our data support sexual dimorphism in Wnt/β-catenin signaling and PKG2 regulation of this crucial pathway in bone homeostasis. This work establishes PKG2 as a key regulator of osteoblast proliferation and post-natal bone formation.

cDNA Cloning and Gene Expression of Human Type Iα cGMP-Dependent Protein Kinase

Hypertension ◽  
1996 ◽  
Vol 27 (3) ◽  
pp. 552-557 ◽  
Author(s):  
Naohisa Tamura ◽  
Hiroshi Itoh ◽  
Yoshihiro Ogawa ◽  
Osamu Nakagawa ◽  
Masaki Harada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cdna Cloning ◽  
Dependent Protein Kinase ◽  
Human Type ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Chronic Elevation of Calmodulin in the Ventricles of Transgenic Mice Increases the Autonomous Activity of Calmodulin-Dependent Protein Kinase II, Which Regulates Atrial Natriuretic Factor Gene Expression

2000 ◽  
Vol 14 (8) ◽  
pp. 1125-1136 ◽  
Author(s):  
Josep M. Colomer ◽  
Anthony R. Means
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Transgenic Mice ◽  
Atrial Natriuretic Factor ◽  
Ventricular Myocytes ◽  
Dependent Protein Kinase ◽  
Natriuretic Factor ◽  
Dependent Protein ◽  
Autonomous Activity

Abstract Although isoforms of Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been implicated in the regulation of gene expression in cultured cells, this issue has yet to be addressed in vivo. We report that the overexpression of calmodulin in ventricular myocytes of transgenic mice results in an increase in the Ca2+/calmodulin-independent activity of endogenous CaMKII. The calmodulin transgene is regulated by a 500-bp fragment of the atrial natriuretic factor (ANF) gene promoter which, based on cell transfection studies, is itself known to be regulated by CaMKII. The increased autonomous activity of CaMKII maintains the activity of the transgene and establishes a positive feedforward loop, which also extends the temporal expression of the endogenous ANF promoter in ventricular myocytes. Both the increased activity of CaMKII and transcriptional activation of ANF are highly selective responses to the chronic overexpression of calmodulin. These results indicate that CaMKII can regulate gene expression in vivo and suggest that this enzyme may represent the Ca2+-dependent target responsible for reactivation of the ANF gene during ventricular hypertrophy.

scholarly journals cGMP-dependent protein kinase and the regulation of vascular smooth muscle cell gene expression: possible involvement of Elk-1 sumoylation

2010 ◽  
Vol 299 (5) ◽  
pp. H1660-H1670 ◽  
Author(s):  
ChungSik Choi ◽  
Hassan Sellak ◽  
Felricia M. Brown ◽  
Thomas M. Lincoln
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Specific Gene ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Vascular Smcs ◽  
Dependent Protein

Although the regulation of smooth muscle cell (SMC) gene expression by cGMP-dependent protein kinase (PKG) is now recognized, the mechanisms underlying these effects are not fully understood. In this study, we report that PKG-I stimulates myocardin/serum response factor (SRF)-dependent gene expression in vascular SMCs. The expression of PKG in PKG-deficient cells enhanced myocardin-induced SM22 promoter activity in a concentration-dependent fashion. However, neither SRF nor myocardin expression was affected. To investigate alternative mechanisms, we examined whether PKG affects the phosphorylation of E26-like protein-1 (Elk-1), a SRF/myocardin transcription antagonist. The activation of PKG caused an increase in a higher molecular mass form of phospho-Elk-1 that was determined to be small ubiquitin-related modifier (sumo)ylated Elk-1. PKG increased Elk-1 sumoylation twofold compared with the PKG-deficient cells, and Elk-1 sumoylation was reduced using dominant-negative sumo-conjugating enzyme, DN-Ubc9, confirming PKG-dependent sumoylation of phospho-Elk-1 in vascular SMCs. In addition, PKG stimulated Elk-1 sumoylation in COS-7 cells overexpressing Elk-1, sumo-1, and PKG-I. The increased expression of PKG in vascular SMCs inhibited Elk-1 binding to SMC-specific promoters, SM22 and smooth muscle myosin heavy chain, as measured by EMSA and chromatin immunoprecipitation assay, and PKG suppressed the Elk-1 inhibition of SM22 reporter gene expression. Taken together, these data suggest that PKG-I decreases Elk-1 activity by sumo modification of Elk-1, thereby increasing myocardin-SRF activity on SMC-specific gene expression.

scholarly journals Regulation of Gene Expression by cGMP-dependent Protein Kinase

1996 ◽  
Vol 271 (9) ◽  
pp. 4597-4600 ◽  
Author(s):  
Tanima Gudi ◽  
Ivana Huvar ◽  
Matthias Meinecke ◽  
Suzanne M. Lohmann ◽  
Gerry R. Boss ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Regulation Of Gene Expression ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Overexpression of cGMP-dependent protein kinase I (PKG-I) attenuates ischemia-reperfusion-induced kidney injury

2012 ◽  
Vol 302 (5) ◽  
pp. F561-F570 ◽  
Author(s):  
Yanzhang Li ◽  
Xiaopeng Tong ◽  
Hasiyeti Maimaitiyiming ◽  
Kate Clemons ◽  
Ji-Min Cao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transgenic Mice ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

cGMP-dependent protein kinase (PKG) is a multifunctional protein. Whether PKG plays a role in ischemia-reperfusion-induced kidney injury (IRI) is unknown. In this study, using an in vivo mouse model of renal IRI, we determined the effect of renal IRI on kidney PKG-I levels and also evaluated whether overexpression of PKG-I attenuates renal IRI. Our studies demonstrated that PKG-I levels (mRNA and protein) were significantly decreased in the kidney from mice undergoing renal IRI. Moreover, PKG-I transgenic mice had less renal IRI, showing improved renal function and less tubular damage compared with their wild-type littermates. Transgenic mice in the renal IRI group had decreased tubular cell apoptosis accompanied by decreased caspase 3 levels/activity and increased Bcl-2 and Bag-1 levels. In addition, transgenic mice undergoing renal IRI demonstrated reduced macrophage infiltration into the kidney and reduced production of inflammatory cytokines. In vitro studies showed that peritoneal macrophages isolated from transgenic mice had decreased migration compared with control macrophages. Taken together, these results suggest that PKG-I protects against renal IRI, at least in part through inhibiting inflammatory cell infiltration into the kidney, reducing kidney inflammation, and inhibiting tubular cell apoptosis.

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