Exogenous bone morphogenetic protein-7 fails to attenuate renal fibrosis in rats with overload proteinuria.

Abstract

BACKGROUND: Bone morphogenetic protein-7 (BMP-7) plays a critical role in renal development, accelerates recovery from acute renal injury, and more recently it has been shown to delay progressive renal disease. The present study was designed to investigate the effect of BMP-7 on interstitial fibrosis in the rat protein-overloaded model.

METHODS: Renal disease was induced in 26 rats by daily intraperitoneal injections of bovine serum albumin (BSA); controls (n = 28) were injected with saline. Half of the rats in each group were treated with human recombinant BMP-7 (300 microg/kg i.p. 3 times weekly) and half with placebo. Animals were killed after 3 or 6 weeks.

RESULTS: Compared to the saline control groups, the BSA groups had evidence of chronic renal disease: significantly increased urinary protein excretion rates; total kidney collagen content, and increased fibronectin and collagen III interstitial areas. By 6 weeks the BSA + BMP-7 group compared to the BSA + placebo group had a nonsignificant decrease in blood urea nitrogen (40 +/- 13 vs. 46 +/- 11 mg/dl), total kidney collagen (10.8 +/- 2.1 vs. 12.2 +/- 3.5 microg/kidney), fibronectin interstitial area (23 +/- 4 vs. 25 +/- 8%) and collagen III interstitial area (22 +/- 6 vs. 28 +/- 7%). Despite these results, renal gene expression profiles actually predicted worse fibrosis in the BSA + BMP-7 group with significantly higher total kidney mRNA levels for alpha(1)(III) procollagen (2.8 +/- 0.5 vs. 1.6 +/- 0.6, p < 0.05) and fibronectin at 6 weeks (1.9 +/- 0.3 vs. 1.2 +/- 0.5, p < 0.05). Renal BMP-7 mRNA levels at 6 weeks were significantly increased in the BSA + placebo group compared to the saline + placebo group with no difference between the BSA + BMP-7 and the BSA + placebo groups. Both cortical and medullary tubules expressed BMP-7 protein but BMP-7 was only detected in the tubular lumina and urine of proteinuric animals.

CONCLUSIONS: In rats with protein-overload proteinuria, renal tubules continue to express BMP-7 but some of the endogenous protein is secreted into the urinary space. Administration of exogenous recombinant BMP-7 had no effect on proteinuria but was associated with a nonsignificant trend towards less interstitial fibrosis at 6 weeks despite significantly higher kidney extracellular matrix gene mRNA levels. These findings suggest that BMP-7 treatment may have anti-fibrotic effects through enhancement of matrix turnover, although overall these effects are modest in proteinuric states in the absence of significant tubular epithelial cell apoptosis and epithelial-mesenchymal transition.