title: CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway.
abstract: 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 (PPRAγ) pathway in DN. In high glucose cultured NRK52E cells, blocking CDK5 activity inhibited epithelial-to-mesenchymal transition (EMT) and fibrosis via ERK1/2/PPARγ 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 β2-microglobulin. Further studies revealed that improved renal fibrosis and function in diabetic rats were associated with inactivation of ERK1/2 and PPARγ signaling pathways. In late staged DN patients, the upregulation of CDK5 and p35 activated phosphorylated ERK1/2 and PPARγ, 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, β2-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/PPARγ pathway and EMT in DN. CDK5 might have therapeutic potential in diabetic nephropathy.
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Bai
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, PR China.|Division of Nephrology, The First Affiliated Hospital, Inner Mongolia Medical University, Hohhot, Inner Mongolia, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hou
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, PR China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose
keywords: CDK5; ERK1/2; PPARγ; diabetic nephropathy; tubulointerstitial fibrosis