LY333531, a PKCß inhibitor, attenuates glomerular endothelial cell apoptosis in the early stage of mouse diabetic nephropathy via down-regulating swiprosin-1.
Acta Pharmacol Sin
; 38(7): 1009-1023, 2017 Jul.
Article
in En
| MEDLINE
| ID: mdl-28414198
ABSTRACT
Glomerular endothelial cell (GEC) injury plays an important role in the early stage of diabetic nephropathy (DN). Previous studies show that a PKCß inhibitor is effective for treating DN. In the current study we further explored the effects and molecular mechanisms of PKCß inhibitors on GEC apoptosis in DN in streptozotocin-induced diabetic mice in vivo and high glucose- or PMA-treated human renal glomerular endothelial cells (HRGECs) in vitro. In the diabetic mice, hyperglycemia caused aggravated nephropathy and GEC apoptosis accompanied by significantly increased expression of swiprosin-1, a potentally pro-apoptotic protein. Administration of LY333531 (1 mg·kg-1·d-1 for 8 weeks) significantly attenuated both GEC apoptosis and swiprosin-1 upregulation in the diabetic mice. Similar results were observed in high glucose- or PMA-treated HRGECs in vitro. The pro-apoptotic role of swiprosin-1 was further examined using HRGECs treated with lentivirus mediating RNA interference or over-expression and swiprosin-1-knockout mice. Over-expression of swiprosin-1 in HRGECs resulted in increases in apoptosis and in caspase-9, caspase-3 and Bax expression. In contrast, knockdown of swiprosin-1 attenuated high glucose- or PMA-induced HRGECs apoptosis. Furthermore, over-expression of swiprosin-1 promoted interaction between swiprosin-1 and caspase-9 and increased the formation of apoptosomes. In diabetic swiprosin-1-/- mice, the kidney/body weight, urinary albumin, glomerular hypertrophy, mitochondrial apoptotic-associated proteins and GEC apoptosis were significantly attenuated as compared with those in diabetic swiprosin-1+/+ mice. These results demonstrate that swiprosin-1 is up-regulated by PKCß in the early stage of DN, and that PKCß facilitates GEC apoptosis through the mitochondrial-dependent pathway.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinase C
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Calcium-Binding Proteins
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Down-Regulation
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Apoptosis
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Protein Kinase Inhibitors
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Diabetic Nephropathies
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Kidney Glomerulus
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Acta Pharmacol Sin
Journal subject:
FARMACOLOGIA
Year:
2017
Document type:
Article
Affiliation country:
China