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2016 ; 7
(24
): 36510-36528
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CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via
ERK1/2/PPAR? pathway
#MMPMID27145370
Bai X
; Hou X
; Tian J
; Geng J
; Li X
Oncotarget
2016[Jun]; 7
(24
): 36510-36528
PMID27145370
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Cyclin-dependent kinase 5 (CDK5) has been documented in podocyte injuries in
diabetic nephropathy (DN), however its role in renal tubular epithelial cells has
not been elucidated. We report here that CDK5 is detrimental and promotes
tubulointerstitial fibrosis (TIF) via the extracellular signal-regulated kinase
1/2 (ERK1/2)/peroxisome proliferator-activated receptor gamma (PPRA?) pathway in
DN. In high glucose cultured NRK52E cells, blocking CDK5 activity inhibited
epithelial-to-mesenchymal transition (EMT) and fibrosis via ERK1/2/PPAR? pathway.
In diabetic rats, CDK5 inhibitor roscovitine decreased renal fibrosis and
improved renal function as demonstrated by a decrease in levels of blood urine
nitrogen (BUN), serum creatinine and ?2-microglobulin. Further studies revealed
that improved renal fibrosis and function in diabetic rats were associated with
inactivation of ERK1/2 and PPAR? signaling pathways. In late staged DN patients,
the upregulation of CDK5 and p35 activated phosphorylated ERK1/2 and PPAR?,
leading to decreased levels of E-cadherin but increased Vimentin and Collagen IV.
Accordingly, renal fibrosis and function were worsened as revealed by decreased
estimated glomerular filtration rate (eGFR) and increased serum BUN, creatinine,
?2-microglobulin, 24-hour proteinuria and urine albumin to creatinine ratio
(UACR). These findings demonstrate a novel mechanism that CDK5 increases
tubulointerstitial fibrosis by activating the ERK1/2/PPAR? pathway and EMT in DN.
CDK5 might have therapeutic potential in diabetic nephropathy.
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