Tangshen formula attenuates diabetic renal injuries by upregulating autophagy via inhibition of PLZF expression

PLoS One. 2017 Feb 9;12(2):e0171475. doi: 10.1371/journal.pone.0171475. eCollection 2017.

Abstract

The Chinese herbal granule Tangshen Formula (TSF) has been proven to decrease proteinuria and improve estimated glomerular filtration rate (eGFR) in diabetic kidney disease (DKD) patients. However, the underlying mechanism of TSF on treatment of diabetic nephropathy (DN) remains unclear. The present study aimed to identify the therapeutic target of TSF in diabetic renal injuries through microarray-based gene expression profiling and establish its underlying mechanism. TSF treatment significantly attenuated diabetic renal injuries by inhibiting urinary excretion of albumin and renal histological injuries in diabetic (db/db) mice. We found that PLZF might be the molecular target of TSF in DN. In vivo, the db/db mice showed a significant increase in renal protein expression of PLZF and collagen III, and decrease in renal autophagy levels (downregulated LC3 II and upregulated p62/SQSTM1) compared to db/m mice. The application of TSF resulted in the downregulation of PLZF and collagen III and upregulation of autophagy level in the kidneys of db/db mice. In vitro, TSF reduced high glucose (HG)-induced cell proliferation for NRK52E cells. Further studies indicated that the exposure of NRK52E cells to high levels of glucose resulted in the downregulation of cellular autophagy and upregulation of collagen III protein, which was reversed by TSF treatment by decreasing PLZF expression. In conclusion, TSF might have induced cellular autophagy by inhibiting PLZF expression, which in turn resulted in an increase in autophagic degradation of collagen III that attenuated diabetic renal injuries.

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Cell Line
  • Collagen Type III / genetics
  • Collagen Type III / metabolism
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Drugs, Chinese Herbal / pharmacology*
  • Drugs, Chinese Herbal / therapeutic use
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Promyelocytic Leukemia Zinc Finger Protein
  • Proteolysis
  • Rats
  • Up-Regulation

Substances

  • Collagen Type III
  • Drugs, Chinese Herbal
  • Hypoglycemic Agents
  • Kruppel-Like Transcription Factors
  • Promyelocytic Leukemia Zinc Finger Protein
  • Zbtb16 protein, mouse

Grants and funding

This work was supported by grants from a Project of International Cooperation and Exchange of the National Natural Science Foundation of China (Grant No. 81620108031 to PL), http://www.nsfc.gov.cn/; a Project of International Collaboration in Science and Technology Grant, China (Grant No. 2011DFA31860 to PL), http://www.istcp.org.cn/; and the National Natural Science Foundation of China (Grant No. 81503418 to HLZ, No. 81473526 to TTZ), http://www.nsfc.gov.cn/.