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.
Highlights
Diabetic nephropathy (DN) was one of the major microvascular complications of type 2 diabetes mellitus (T2DM) and was a major cause of end-stage renal disease (ESRD)
Mesangial matrix expansion and extracellular matrix deposition were observed in the kidneys of the db/db mice, and these histological injuries were significantly ameliorated in the db/db mice that were treated with Tangshen Formula (TSF) (Fig 1B and 1C)
Compared to the db/db mice, 9 genes were upregulated and 4 genes were downregulated in the db/db mice treated with TSF (Fig 2), of which 3 genes were differentially expressed among the 3 groups: Pgm5, Zbtb16/PLZF, and Abcb1b
Summary
Diabetic nephropathy (DN) was one of the major microvascular complications of type 2 diabetes mellitus (T2DM) and was a major cause of end-stage renal disease (ESRD). Key pathological features of DN included glomerular hypertrophy, as well as extracellular matrix (ECM) deposition in the mesangium and tubulointerstitium [1]. Microalbuminuria was considered to be an important marker of DN, which reflected glomerular injuries but PLOS ONE | DOI:10.1371/journal.pone.0171475. Microalbuminuria was considered to be an important marker of DN, which reflected glomerular injuries but PLOS ONE | DOI:10.1371/journal.pone.0171475 February 9, 2017
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