Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy

Song Wang, Qing Chen, Theodore C. Simon, Frank Strebeck, Lala Chaudhary, Jeremiah Morrissey, Helen Liapis, Saulo Klahr, Keith A. Hruska

Research output: Contribution to journalArticle

195 Scopus citations

Abstract

Background. Bone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD). Methods. Diabetes was induced in 200 g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 μg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured. Results. Diabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34 ± 0.02 mL/min/100 g body weight vs. 0.55 ± 0.02 in normal). In the diabetic BMP-7 high-dose-treated rats, GFR was preserved (0.70 ± 0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58 ± 0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels. Conclusion. BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.

Original languageEnglish
Pages (from-to)2037-2049
Number of pages13
JournalKidney International
Volume63
Issue number6
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

Keywords

  • BMP-7
  • Chronic kidney disease
  • Diabetic nephropathy

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