Journal
ONCOTARGET
Volume 7, Issue 24, Pages 36510-36528Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9058
Keywords
CDK5; ERK1/2; PPAR gamma; tubulointerstitial fibrosis; diabetic nephropathy
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Funding
- National Nature and Science Young Investigator Grant from the National Natural Science Foundation of China [81100496]
- National Natural Science Foundation of China from Nanfang Hospital, Southern Medical University [G201203]
- Special Fund from Chinese Society of Nephrology [13030370422]
- Key Clinical Specialty Discipline Construction Program
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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 (PPAR gamma) pathway in DN. In high glucose cultured NRK52E cells, blocking CDK5 activity inhibited epithelial-to-mesenchymal transition (EMT) and fibrosis via ERK1/2/PPAR gamma 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 beta 2-microglobulin. Further studies revealed that improved renal fibrosis and function in diabetic rats were associated with inactivation of ERK1/2 and PPAR gamma signaling pathways. In late staged DN patients, the upregulation of CDK5 and p35 activated phosphorylated ERK1/2 and PPAR gamma, 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, beta 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 gamma pathway and EMT in DN. CDK5 might have therapeutic potential in diabetic nephropathy.
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