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


CONCLUSIONS
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.
Wang
Song
S
Renal Division, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Chen
Qing
Q
Simon
Theodore C
TC
Strebeck
Frank
F
Chaudhary
Lala
L
Morrissey
Jeremiah
J
Liapis
Helen
H
Klahr
Saulo
S
Hruska
Keith A
KA
D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta
C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D018696:Neuroprotective Agents; D016212:Transforming Growth Factor beta