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Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
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Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice

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CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway

Xiaoyan Bai1, Xiaoyan Hou1,2, Jianwei Tian1

  • 1Division 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.

Oncotarget
|May 5, 2016
PubMed

Insights

Cyclin-dependent kinase 5 (CDK5) drives kidney tubulointerstitial fibrosis in diabetic nephropathy by activating the ERK1/2/PPARγ pathway. Inhibiting CDK5 shows therapeutic potential for improving kidney function in diabetic kidney disease.

Area of Science:

  • Nephrology
  • Cell Biology
  • Biochemistry

Background:

  • Diabetic nephropathy (DN) involves podocyte injury, but the role of Cyclin-dependent kinase 5 (CDK5) in renal tubular epithelial cells remains unclear.
  • CDK5 is implicated in podocyte damage in DN.

Purpose of the Study:

  • To investigate the role of CDK5 in renal tubular epithelial cells in diabetic nephropathy (DN).
  • To elucidate the underlying molecular mechanisms, specifically the extracellular signal-regulated kinase 1/2 (ERK1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) pathway.

Main Methods:

  • Utilized high glucose cultured NRK52E cells to study CDK5 inhibition effects on epithelial-to-mesenchymal transition (EMT) and fibrosis.
  • Administered CDK5 inhibitor roscovitine to diabetic rats to assess impacts on renal fibrosis and function markers.
  • Analyzed renal tissue and serum from late-stage DN patients to correlate CDK5, p35, ERK1/2, PPARγ, and fibrosis markers.

Main Results:

  • Blocking CDK5 in high glucose conditions inhibited EMT and fibrosis via the ERK1/2/PPARγ pathway.
  • Roscovitine treatment in diabetic rats reduced renal fibrosis and improved renal function, indicated by decreased BUN, serum creatinine, and β2-microglobulin.
  • DN patients showed upregulated CDK5/p35, activated ERK1/2/PPARγ, increased Vimentin and Collagen IV, decreased E-cadherin, and worsened renal function (eGFR, proteinuria, UACR).

Conclusions:

  • CDK5 promotes tubulointerstitial fibrosis in diabetic nephropathy by activating the ERK1/2/PPARγ pathway and inducing EMT.
  • CDK5 inhibition represents a potential therapeutic strategy for managing diabetic nephropathy.
Keywords:
CDK5ERK1/2PPARγdiabetic nephropathytubulointerstitial fibrosis

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