The significance of glomerular cyclin-kinase inhibitor p27 in diabetic rats

A precise balance between proliferation and differentiation must be maintained during retinal development to obtain the correct proportion of each of the seven cell types found in the adult tissue. Cyclin kinase inhibitors can regulate cell cycle exit coincident with induction of differentiation programs during development. We have found that the p57(Kip2) cyclin kinase inhibitor is upregulated during G(1)/G(0) in a subset of retinal progenitor cells exiting the cell cycle between embryonic day 14.5 and 16.5 of mouse development. Retroviral mediated overexpression of p57(Kip2) in embryonic retinal progenitor cells led to premature cell cycle exit. Retinae from mice lacking p57(Kip2) exhibited inappropriate S-phase entry and apoptotic nuclei were found in the region where p57(Kip2) is normally expressed. Apoptosis precisely compensated for the inappropriate proliferation in the p57(Kip2)-deficient retinae to preserve the correct proportion of the major retinal cell types. Postnatally, p57(Kip2) was found to be expressed in a novel subpopulation of amacrine interneurons. At this stage, p57(Kip2)did not regulate proliferation. However, perhaps reflecting its role during this late stage of development, animals lacking p57(Kip2) showed an alteration in amacrine subpopulations. p57(Kip2) is the first gene to be implicated as a regulator of amacrine subtype/subpopulation development. Consequently, we propose that p57(Kip2) has two roles during retinal development, acting first as a cyclin kinase inhibitor in mitotic progenitor cells, and then playing a distinct role in neuronal differentiation.

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Abstract 115: Reduction of Trpv1 Activity in Aortic Baroreceptor Neurons in Diabetic Neuropathy: Role of Brain-derived Neurotrophic Factor

Hypertension ◽

10.1161/hyp.60.suppl_1.a115 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Yingying Tan ◽

Qi Zhang

Keyword(s):

Diabetic Neuropathy ◽

Transient Receptor Potential ◽

Kinase Inhibitor ◽

Receptor Potential ◽

Diabetic Rats ◽

Control Group ◽

Transient Receptor Potential Vanilloid ◽

Peak Current Density ◽

Inward Current ◽

Pre Treatment

It has been well documented that diabetes mellitus is associated with cardiovascular autonomic neuropathy including dysfunction of arterial baroreflex. The mechanisms underlying diabetes-induced baroreflex dysfunction remain poorly understood. Here we investigated the function and expression of transient receptor potential vanilloid 1 (TRPV1) in aortic baroreceptor (AB) neurons isolated from streptozotocin-induced diabetic rats between 4 and 8 weeks after onset of diabetes. AB neurons in nodose ganglion were retrograde-labeled by a transported fluorescent dye, Dil. Using the whole-cell patch clamp, we found that the inward current activated by the application of capsaicin (1 μM) was significantly smaller in AB neurons from diabetic rats compared with controls. The mean peak current density of capsaicin-induced currents was 145.7 ± 24.7 pA/pF (n = 16) in diabetic neurons and 269.3 ± 31.8 pA/pF (n =15) in controls, respectively. The duration of inward current was decreased 51% in diabetic rats compared with the control group. These evoked currents were completely blocked by the capsaicin antagonist capsazepine. In addition, capsaicin-induced desensitization of TRPV1 was up-regulated, whereas TRPV1 re-sensitization was down-regulated in AB neurons from diabetic rats. Immunofluorescence staining studies demonstrated that the percentage of TRPV1-positive neurons was 50.2 ± 5.0% in control rats and 38.2 ± 1.9% in diabetic rats, respectively. This reduction in TRPV1-positive neurons in AB neurons in diabetic rats was significant (n = 11, P < 0.01). In addition, the reductions in TRPV1 currents and positive neurons s in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. Furthermore, incubation with BDNF caused a large reduction in TRPV1 currents in AB neurons from control rats, and the number of AB neurons with BDNF immunoreactivity was greater in diabetic than control rats. These results suggest that reduced expression and function of TRPV1 are involved in the attenuation of baroreceptor neuron excitability, and increased BDNF activity in these neurons likely contributes to the reduction in TRPV1 function through TrkB receptor stimulation in diabetic neuropathy.

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The effect of spleen tyrosine kinase inhibitor R406 on diabetic retinopathy in experimental diabetic rats

International Ophthalmology ◽

10.1007/s10792-020-01422-4 ◽

2020 ◽

Vol 40 (9) ◽

pp. 2371-2383

Author(s):

Xian Su ◽

Zhao-Hui Sun ◽

Qian Ren ◽

Jun-Ru Liu ◽

Li Yin ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Diabetic Rats ◽

Spleen Tyrosine Kinase

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Attenuation of matrix protein secretion by antisense oligodeoxynucleotides to the cyclin kinase inhibitor p21Waf1/Cip1

Atherosclerosis ◽

10.1016/s0021-9150(01)00628-1 ◽

2002 ◽

Vol 161 (1) ◽

pp. 105-112 ◽

Cited By ~ 8

Author(s):

Robert H Weiss ◽

Collette J Randour

Keyword(s):

Protein Secretion ◽

Matrix Protein ◽

Kinase Inhibitor ◽

Antisense Oligodeoxynucleotides ◽

Cyclin Kinase Inhibitor

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The tyrosine kinase inhibitor crizotinib influences blood glucose and mRNA expression of GLUT4 and PPARs in the heart of rats with experimental diabetes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0572 ◽

2020 ◽

Author(s):

Katarina Hadova ◽

Lucia Mesarosova ◽

Eva Kralova ◽

Gabriel Doka ◽

Peter Krenek ◽

...

Keyword(s):

Blood Glucose ◽

Mrna Expression ◽

Tyrosine Kinases ◽

Glucose Transporter ◽

Kinase Inhibitor ◽

Experimental Diabetes ◽

Cardiac Metabolism ◽

Diabetic Rats ◽

C Peptide ◽

Glucose Transporter Glut4

Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80 mg/kg, i.p.), controls received vehicle (CON). Three days after STZ, crizotinib (STZ+CRI; 25 mg/kg/day p.o.) or vehicle was administered for 7 days. Blood glucose, C-peptide and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters and PPARs were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P<0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.

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