The Protective Effect of Plzf and Annexin A1 on Diabetic Tubulopathy in the Pparα Signaling Pathway

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details


Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide. As its prevalence is increasing, no promising therapeutic options are available currently. In most glomerulopathic disease, the degree of tubulointerstitial injury correlates renal function more than that of the glomerular lesion. Diffuse diabetes-induced glomerular damage results in pathological proteinuria, but renal tubulointerstitium also plays an important role in the genesis of DN. The development of drugs for ameliorating diabetic tubulopathy remains valuable in biomedical research. Advanced glycation end products (AGEs) are thought to be the major causes of different diabetic complications. AGEs enter proximal tubule epithelial cells and accumulate in proximal tubule epithelial cells to stimulate TGF-β release. TGF-β is a profibrotic cytokine found in chronic kidney diseases. The intracellular macromolecules are degraded and recycled by the autophagic-lysosomal pathway. Autophagy serves as an essential mechanism to maintain homeostasis of glomeruli and tubules, and plays important roles in human health and diseases. Targeting the autophagic pathway to activate and restore autophagy activity may be renoprotective. Peroxisome proliferator-activated receptor-alpha (PPARα) is a nuclear receptor for long-chain fatty acids and various fatty acid-derived compounds, which protects renal tubular cells from apoptotic injury. Recently, we found that PPARα activation increased promyelocytic leukemia zinc finger protein (PLZF) expression in rat renal tubular cells. PLZF is a nuclear transcription factor belonging to the BTB/POZ family. PLZF activation upregulated PI3Ks (classes I and III) involved in autophagic signaling. PPARα-induced PLZF upregulation is potential to induce autophagy in renal tubular cells and reduce AGE-induced injury. On the other hand, we also found that PPARα activation significantly reduced annexin A1 (Anx A1) in renal tubular cells. Expression of Anx A1 induces activation of the TGF-β pathway. The reduction of Anx A1 may play a role in the anti-fibrotic effect of PPARα in renal tubular cells. We hypothesized that PPARα might reduce AGE-induced fibrotic responses and injury in renal tubular cells through inducing PLZF-mediated autophagy and inhibiting Anx A1 pathways. In this 3-year project, we will study the influence of PPARα on AGE-induced renal fibrotic responses and injury in vitro with two systems: (1). An AGE-induced injury model with rat renal tubular cells (NRK-52E). (2). A TGF-β-induced fibrosis model with NRK-52E cells. Furthermore, we established a type 2 diabetes mouse model (treated with nicotinamide/ streptozotocin) and used PPARα knockout mice to test the effect of PPARα activation on diabetic nephropathy. The specific aims of this project are listed below: 1. To identify the influence of PPARα activation on AGE-induced renal fibrotic responses and injury. 2. To identify the influence of PPARα activation on TGF-β-induced fibrotic signal transduction in NRK-52E cells. 3. To investigate the involvement of PLZF-mediated autophagy in inhibitory effect of PPARα activation on AGE-induced renal fibrotic responses and injury. 4. To investigate the involvement of Anx A1 down-regulation in inhibitory effect of PPARα activation on renal fibrotic responses. 5. To investigate the influence of PPARα activation on renal function and fibrosis in a type 2 diabetic mouse model. The investigation of the protective effect of PLZF and annexin A1 on diabetic tubulopathy in the PPARα signaling pathway will provide a potential therapeutic target for DN patients.
Effective start/end date8/1/167/31/17


  • Advanced glycation end products (AGEs)
  • Annexin A1
  • Autophagy
  • Diabetic tubulopathy
  • Peroxisome proliferator-activated receptor-alpha (PPARα)
  • Promyelocytic leukemia zinc finger protein (PLZF)
  • Renal tubular cells


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