The renal expression of epigenetic biomarkers for diabetic nephropathy

The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of theα-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect theα-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreasedα-klotho and VDR renal expression but significantly increased 1-α-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron-mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN.

Download Full-text

Loss of Tubular Bone Morphogenetic Protein—7 in Diabetic Nephropathy

Journal of the American Society of Nephrology ◽

10.1681/asn.v12112392 ◽

2001 ◽

Vol 12 (11) ◽

pp. 2392-2399 ◽

Cited By ~ 1

Author(s):

SHI-NONG WANG ◽

JANINE LAPAGE ◽

RAIMUND HIRSCHBERG

Keyword(s):

Diabetic Nephropathy ◽

Bone Morphogenetic Protein ◽

Type I ◽

Proximal Tubular Cells ◽

Bone Morphogenetic Protein 7 ◽

Tubular Cells ◽

Morphogenetic Protein ◽

Proximal Tubular ◽

Bmp Antagonist ◽

Renal Expression

Abstract. Bone morphogenetic protein—7 (BMP7), a member of the transforming growth factor—β (TGF—β) superfamily of cytokines, is highly expressed in renal tubules and generally promotes maintenance of epithelial phenotype. It was examined whether, during the evolution of experimental diabetic nephropathy, the renal expression of BMP7 and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is profibrogenic in proximal tubular cells was tested. Moreover,in vitrostudies in cultured proximal tubular cells were performed to examine putative mechanisms that cause these changes. At 15 wk of streptozotocin-induced diabetes, renal expression of BMP7 is declined by about half, and it decreased further by 30 wk to <10% of timed controls. Renal expression of the high-affinity BMP type II receptor and the type I receptor Alk2 (activin receptor—like kinase-2) decreased. Alk3 tended to decrease, but Alk6 remained unchanged. During the evolution of diabetic nephropathy, the secreted BMP antagonist gremlin increased substantially. In cultured tubular cells, TGF-β reduced BMP7 and Alk3 expression and increased gremlin but did not interrupt BMP7-induced activation of smad5 or Erk1 and -2. In contrast, BMP7 did not alter TGF-β expression. Neutralization of endogenous BMP7 in cultured proximal tubular cells raised the expression of fibronectin and tended to increase collagen α1III mRNA levels. In conclusion, in experimental diabetic nephropathy, renal tubular BMP7 and some of its receptors decreased and gremlin, a secreted BMP antagonist, increased. Some, but not all, of these changes are explained by increased TGF-β. The loss of BMP7 activityper seis profibrogenic in tubular cells.

Download Full-text

Renal expression of cytokines and chemokines in diabetic nephropathy

BMC Nephrology ◽

10.1186/s12882-020-01960-0 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Liliane Silvano Araújo ◽

Bianca Gonçalves Silva Torquato ◽

Crislaine Aparecida da Silva ◽

Maria Luíza Gonçalves dos Reis Monteiro ◽

Ana Luisa Monteiro dos Santos Martins ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Cytokines And Chemokines ◽

Renal Expression

Download Full-text

FP073Methyl-CpG-binding protein 2 binds to Gremlin-1 promoter and represses its renal expression: Potential epigenetic regulation of a key player in diabetic nephropathy development

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz106.fp073 ◽

2019 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Vanessa Marchant ◽

Sergio Mezzano ◽

Bredford Kerr

Keyword(s):

Diabetic Nephropathy ◽

Epigenetic Regulation ◽

Binding Protein ◽

Expression Potential ◽

Renal Expression ◽

Gremlin 1

Download Full-text

Renal expression of proto-oncogene Ets-1 on matrix remodeling in experimental diabetic nephropathy

Acta Histochemica ◽

10.1016/j.acthis.2010.05.006 ◽

2011 ◽

Vol 113 (5) ◽

pp. 527-533 ◽

Cited By ~ 3

Author(s):

Dian-xin Liu ◽

Xiao-min Liu ◽

Ying Su ◽

Xiao-juan Zhang

Keyword(s):

Diabetic Nephropathy ◽

Matrix Remodeling ◽

Renal Expression

Download Full-text

Effects of a GSK-3β inhibitor on the renal expression levels of RANK, RANKL and NF-κB in a rat model of diabetic nephropathy

Experimental and Therapeutic Medicine ◽

10.3892/etm.2016.3184 ◽

2016 ◽

Vol 11 (6) ◽

pp. 2495-2502 ◽

Cited By ~ 2

Author(s):

YI-XIA ZHOU ◽

LI-XIN SHI ◽

HUA YANG ◽

YI-GUO LONG ◽

LU MENG ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Rat Model ◽

Expression Levels ◽

Gsk 3Β ◽

Renal Expression

Download Full-text

C009 Differential renal expression of TGF-$beta; isoforms in the SHR/N-corpulent rat with diabetic nephropathy

American Journal of Hypertension ◽

10.1016/s0895-7061(97)91251-6 ◽

1998 ◽

Vol 11 (4) ◽

pp. 146A

Author(s):

M VELASQUEZ

Keyword(s):

Diabetic Nephropathy ◽

Tgf Beta ◽

Renal Expression

Download Full-text

17β-Estradiol supplementation reduces tubulointerstitial fibrosis by increasing MMP activity in the diabetic kidney

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00375.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. R769-R777 ◽

Cited By ~ 53

Author(s):

Richard W. Mankhey ◽

Corinne C. Wells ◽

Faizah Bhatti ◽

Christine Maric

Keyword(s):

Extracellular Matrix ◽

Diabetic Nephropathy ◽

Tubulointerstitial Fibrosis ◽

Relative Optical Density ◽

Sprague Dawley ◽

Type Iv ◽

Sprague Dawley Rats ◽

Ecm Degradation ◽

17Β Estradiol ◽

Renal Expression

We previously reported that supplementation with 17β-estradiol (E2) attenuates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis in diabetic nephropathy. The present study examined the mechanisms by which E2 regulates extracellular matrix (ECM) metabolism, a process that contributes to the development of glomerulosclerosis and tubulointerstitial fibrosis. The study was performed in female nondiabetic (ND), streptozotocin-induced diabetic (D), and diabetic with E2 supplementation (D+E2) Sprague-Dawley rats for 12 wk. Diabetes was associated with an increase in the renal expression of collagen α type IV [ND, 0.22 ± 0.02; D, 0.99 ± 0.09 relative optical density (ROD); P < 0.05] and fibronectin protein (ND, 0.36 ± 0.08; D, 1.47 ± 0.08 ROD; P < 0.05), as measured by Western blot analysis. E2 supplementation partially attenuated this increase in collagen α type IV (D+E2, 0.47 ± 0.10 ROD) and fibronectin (D+E2, 0.71 ± 0.16 ROD) protein expression associated with D. Diabetes was also associated with a decrease in the expression of matrix metalloproteinase (MMP) isoform MMP-2 (ND, 0.79 ± 0.01; D, 0.62 ± 0.06 ROD; P < 0.05) and MMP-9 protein (ND, 0.49 ± 0.02; D, 0.33 ± 0.03 ROD; P < 0.05). E2 supplementation restored MMP-2 and MMP-9 protein to levels similar or even greater than in the ND kidneys (MMP-2, 0.75 ± 0.06; MMP-9, 0.73 ± 0.01 ROD). The activities of MMP-2 (ND, 7.88 ± 0.44; D, 5.60 ± 0.54 ROD; P < 0.05) and MMP-9 (ND, 29.9 ± 1.8; D, 12.9 ± 2.3 ROD; P < 0.05), as measured by zymography, were also decreased with D. E2 supplementation restored MMP-2 and MMP-9 activity to levels similar to that in ND kidneys (MMP-2, 7.66 ± 0.35; MMP-9, 21.4 ± 2.9 ROD). We conclude that E2 supplementation is renoprotective by attenuating glomerulosclerosis and tubulointerstitial fibrosis by reducing ECM synthesis and increasing ECM degradation.

Download Full-text