Anti-inflammatory role of bone morphogenetic protein 7 in the diabetic kidney

Abstract

Diabetic nephropathy (DN) has become the leading cause of end stage renal disease (ESRD) in developed countries, in which over 90% of the diabetes burden is type 2 in origin. Despite the ever advancing knowledge in the pathogenetic mechanisms of DN, a specific treatment is still lacking and management using contemporary approaches or exploiting newly described therapeutic targets are largely unrewarding. BMP-7 has been reported to confer renal protective effects in acute and chronic kidney disease models, but its potential utility in type 2 diabetic nephropathy remains unknown. In this work, therefore, I hypothesized that BMP-7 confers renal protection that will be explore in vitro in AGE-induced tubular epithelial cells, and in vivo in a murine type 2 DN model. Primary human proximal tubular epithelial cells (PTECs) were growth-arrested and exposed to glycated human serum albumin (AGEs) with or without BMP-7. Inhibitors of different signaling pathways were used to dissect the involvement of each pathway. Nine-week-old db/db mice and their db/m littermates underwent uninephrectomy (Unx) or sham operation, and received BMP-7 (300 μg/kg body weight) or vehicle treatment intraperitoneally every other day for 8 weeks before sacrifice. In cultured human PTECs, exposure to AGEs induced overexpression of ICMA-1, MCP-1, IL-8 and IL-6, involving activation of at least p44/42 and p38 MAPK signaling. BMP-7 dose-dependently attenuated AGE-induced up-regulation of ICMA-1, MCP-1, IL-8 and IL-6 at both mRNA and protein levels. Moreover, BMP-7 suppressed AGE-induced p38 and p44/42 MAPK phosphorylation and reactive oxygen species production in PTECs. Compared with vehicle control, Unx db/db mice treated with BMP-7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3549±816.2 μg/mg vs. 8612±2037 μg/mg, p=0.036), serum BUN (33.26±1.09 mg/dL vs. 37.49±0.89 mg/dL, p=0.006), and renal cortical expression of ICMA-1 and MCP-1 at both gene and protein levels. PAS staining of kidney tissue showed less severe tubular damage and interstitial inflammatory cell infiltration in the BMP-7-treated group. In conclusion, this series of experiments demonstrated that BMP-7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple signaling pro-inflammatory pathways including p38 and p44/42 MAPK. These observations are largely translated in animals with diabetic kidney inflammation. The potential application of BMP-7 as a therapeutic molecule in diabetic nephropathy warrants further investigation and development.