BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy

Abstract

Bone morphogenetic protein 7 (BMP7) has been reported to confer renoprotective effects in acute and chronic kidney disease models, but its potential role in Type 2 diabetic nephropathy remains unknown. In cultured human proximal tubular epithelial cells (PTECs), exposure to advanced glycation end-products (AGEs) induced overexpression of intercellular adhesion molecule 1 (ICAM1), monocyte chemoattractant protein 1 (MCP1), interleukin 8 (IL-8) and interleukin 6 (IL-6), involving activation of p44/42 and p38 mitogen-activated protein kinase (MAPK) signalling. BMP7 dose-dependently attenuated AGE-induced up-regulation of ICAM1, MCP1, IL-8 and IL-6 at both mRNA and protein levels. Moreover, BMP7 suppressed AGE-induced p38 and p44/42 MAPK phosphorylation and reactive oxygen species production in PTECs. Compared with vehicle control, uninephrectomized db/db mice treated with BMP7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3549±816.2 μg/mg compared with 8612±2037 μg/mg, P=0.036), blood urea nitrogen (33.26±1.09 mg/dl compared with 37.49±0.89 mg/dl, P=0.006), and renal cortical expression of ICAM1 and MCP1 at both gene and protein levels. In addition, BMP7-treated animals had significantly less severe tubular damage, interstitial inflammatory cell infiltration, renal cortical p38 and p44/42 phosphorylation and lipid peroxidation. Our results demonstrate that BMP7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple inflammatory signalling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule in diabetic nephropathy warrants further investigation.

Transplantation of adipose‐derived mesenchymal stem cell sheets directly into the kidney suppresses the progression of renal injury in a diabetic nephropathy rat model

“…In the present study, BMP‐7, EGF, HGF, IGF‐1 and PGI 2 secretion was detected in the supernatant of ASC sheets; these factors are known to contribute to the improvement of kidney injury. BMP‐7 has been reported to suppress albuminuria and renal tubule injury by intraperitoneal administration to type 2 diabetes mice. This study concluded that BMP‐7 exerts renoprotective effects by improving the inflammatory response in DN.…”

Quercetin and Vitamin C Mitigate Cobalt Chloride-Induced Hypertension through Reduction in Oxidative Stress and Nuclear Factor Kappa Beta (NF-Kb) Expression in Experimental Rat Model

“…Reduction in protein thiol and non-protein thiol in cardiac and renal tissues observed in this study also suggest oxidative stress, since reduction in thiol content is often associated with oxidative stress [41]. The Fig.…”

Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress

“…Accumulating evidence shows that AGE and RAGE interaction stimulates oxidative stress and promotes renal dysfunction in diabetes. 4 Our previous studies showed that AGE induced tubular inflammation via ROS signaling, 5,13,16 and the evoked oxidative stress could further stimulate RAGE overexpression and potentiate the harmful effect of AGE. Indeed, the crucial role of RAGE in the development and progression of DN has been demonstrated in several animal studies.…”

“…[13][14][15] Furthermore, we recently demonstrated that inhibition of oxidative stress by BMP7 attenuated tubular inflammation and ameliorated renal damage from DN. 16 Kallistatin (KS) was first identified as human tissue kallikrein binding protein that inhibits tissue kallikrein activity toward kininogen and tripeptide substrates. 17 Kallistatin is mostly produced in the liver, and the plasma kallistatin level has been reported to be lower in patients with liver disease and sepsis and in inflammatory bowel disease.…”