The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development

Cyclin-dependent kinase 5 (Cdk5) is expressed in terminally differentiated cells, where it drives development, morphogenesis, and survival. Temporal and spatial kinase activity is regulated by specific activators of Cdk5, dependent on the cell type and environmental factors. In the kidney, Cdk5 is exclusively expressed in terminally differentiated glomerular epithelial cells called podocytes. In glomerular disease, signaling mechanisms via Cdk5 have been addressed by single or combined conventional knockout of known specific activators of Cdk5. A protective, anti-apoptotic role has been ascribed to Cdk5 but not a developmental phenotype, as in terminally differentiated neurons. The effector kinase itself has never been addressed in animal models of glomerular disease. In the present study, conditional and inducible knockout models of Cdk5 were analyzed to investigate the role of Cdk5 in podocyte development and glomerular disease. While mice with podocyte-specific knockout of Cdk5 had no developmental defects and regular lifespan, loss of Cdk5 in podocytes increased susceptibility to glomerular damage in the nephrotoxic nephritis model. Glomerular damage was associated with reduced anti-apoptotic signals in Cdk5-deficient mice. In summary, Cdk5 acts primarily as master regulator of podocyte survival during glomerular disease and—in contrast to neurons—does not impact on glomerular development or maintenance.

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Role of cyclin-dependent kinase 5 in capsaicin-induced cough

European Journal of Pharmacology ◽

10.1016/j.ejphar.2007.03.036 ◽

2007 ◽

Vol 566 (1-3) ◽

pp. 181-184 ◽

Cited By ~ 4

Author(s):

Junzo Kamei ◽

Shun-suke Hayashi ◽

Yoshiki Takahashi ◽

Chihiro Nozaki

Keyword(s):

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase 5

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A ROLE OF POLYMORPHONUCLEAR LEUKOCYTES AND COMPLEMENT IN NEPHROTOXIC NEPHRITIS

Journal of Experimental Medicine ◽

10.1084/jem.122.1.99 ◽

1965 ◽

Vol 122 (1) ◽

pp. 99-116 ◽

Cited By ~ 265

Author(s):

Charles G. Cochrane ◽

Emil R. Unanue ◽

Frank J. Dixon

Keyword(s):

Polymorphonuclear Leukocytes ◽

Basement Membranes ◽

Ultrastructural Changes ◽

Glomerular Injury ◽

Large Numbers ◽

Secondary Stage ◽

Vascular Beds ◽

Nephrotoxic Nephritis ◽

Glomerular Damage

In acute nephrotoxic nephritis, polymorphonuclear leukocytes (polymorphs) accumulated in large numbers in the glomeruli in the first 12 hours. The endothelial cells were dislodged by the polymorphs which then came to lie immediately adjacent to the glomerular basement membranes. Ultrastructural changes in neither polymorphs nor basement membranes were observed. Depletion of polymorphs in both rats and rabbits prevented the development of proteinuria. This occurred when doses of nephrotoxic globulin were employed that produced proteinurias of as much as 1800 mg/kg/24 hours in intact rabbits, or enough to yield near maximal immediate proteinuria in intact rats. In addition, measurable glomerular damage was frequently averted until the onset of the secondary stage of NTN. Controls indicated that the polymorph depleted animals exhibited minimal non-specific changes in the blood, that the ability of their vascular beds to react to stimuli was not affected, and that deposition of nephrotoxic antibody and C' in the glomeruli was not inhibited. Elimination of polymorphs from the circulation was only partially effective in preventing glomerular damage when large doses of nephrotoxic globulin were used. This indicated that under these circumstances, a polymorph independent glomerular injury may also take place in first stage nephrotoxic nephritis. An indirect role of C', i.e., the accumulation of polymorphs, in bringing about glomerular injury in first stage nephrotoxic nephritis was apparent. When rabbit nephrotoxic globulin was injected into rats depleted of C', or when duck nephrotoxic globulin that fixed C' poorly was injected into normal rats, C' failed to bind with the antibody along glomerular basement membranes and polymorphs did not accumulate.

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Alzheimer Disease and Related Tauopathies: Possible Neuroprotective Strategies

Neuroscience and Neurological Surgery ◽

10.31579/2578-8868/032 ◽

2018 ◽

Vol 2 (3) ◽

pp. 01-02

Author(s):

Meketa Muñoz

Keyword(s):

Alzheimer Disease ◽

Glycogen Synthase ◽

Vital Role ◽

Current Therapy ◽

Cyclin Dependent Kinase ◽

Abnormal Hyperphosphorylation ◽

Neuroprotective Strategies ◽

Gsk 3Β ◽

Cyclin Dependent Kinase 5

Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.

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Is there a role of the cyclin-dependent kinase 5 activator p25 in Alzheimer??s disease?

Neuroreport ◽

10.1097/01.wnr.0000185019.67434.d2 ◽

2005 ◽

Vol 16 (16) ◽

pp. 1725-1730 ◽

Cited By ~ 24

Author(s):

K. Peter Giese ◽

Laurence Ris ◽

Florian Plattner

Keyword(s):

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase 5

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The role of cyclin-dependent kinase 5 and a novel regulatory subunit in regulating muscle differentiation and patterning.

Genes & Development ◽

10.1101/gad.11.11.1409 ◽

1997 ◽

Vol 11 (11) ◽

pp. 1409-1421 ◽

Cited By ~ 79

Author(s):

A Philpott ◽

E B Porro ◽

M W Kirschner ◽

L H Tsai

Keyword(s):

Muscle Differentiation ◽

Regulatory Subunit ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase 5

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Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety

Nature Communications ◽

10.1038/ncomms8660 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 81

Author(s):

Guo-Qiang Wang ◽

Cheng Cen ◽

Chong Li ◽

Shuai Cao ◽

Ning Wang ◽

...

Keyword(s):

Chronic Pain ◽

Prelimbic Cortex ◽

Cyclin Dependent Kinase ◽

Pain Sensation ◽

Pain Model ◽

Excitatory Neurons ◽

Affective Pain ◽

Underlying Mechanisms ◽

Cyclin Dependent Kinase 5

Abstract The medial prefrontal cortex (mPFC) is implicated in processing sensory-discriminative and affective pain. Nonetheless, the underlying mechanisms are poorly understood. Here we demonstrate a role for excitatory neurons in the prelimbic cortex (PL), a sub-region of mPFC, in the regulation of pain sensation and anxiety-like behaviours. Using a chronic inflammatory pain model, we show that lesion of the PL contralateral but not ipsilateral to the inflamed paw attenuates hyperalgesia and anxiety-like behaviours in rats. Optogenetic activation of contralateral PL excitatory neurons exerts analgesic and anxiolytic effects in mice subjected to chronic pain, whereas inhibition is anxiogenic in naive mice. The intrinsic excitability of contralateral PL excitatory neurons is decreased in chronic pain rats; knocking down cyclin-dependent kinase 5 reverses this deactivation and alleviates behavioural impairments. Together, our findings provide novel insights into the role of PL excitatory neurons in the regulation of sensory and affective pain.

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Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase.

Journal of the American Society of Nephrology ◽

10.1681/asn.v8111712 ◽

1997 ◽

Vol 8 (11) ◽

pp. 1712-1721 ◽

Cited By ~ 1

Author(s):

V Bremer ◽

A Tojo ◽

K Kimura ◽

Y Hirata ◽

A Goto ◽

...

Keyword(s):

Nitric Oxide ◽

Early Stage ◽

Renal Tissue ◽

Macrophage Infiltration ◽

Intercellular Adhesion Molecule ◽

No Production ◽

Sprague Dawley ◽

Nephrotoxic Nephritis ◽

Glomerular Damage

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.

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