TY - JOUR
T1 - Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy
AU - Wang, Song
AU - Chen, Qing
AU - Simon, Theodore C.
AU - Strebeck, Frank
AU - Chaudhary, Lala
AU - Morrissey, Jeremiah
AU - Liapis, Helen
AU - Klahr, Saulo
AU - Hruska, Keith A.
N1 - Funding Information:
The studies in this manuscript were supported by grants from the NIH, DK59602, DK09976, and from the NIH-supported Diabetes Research and Training Center, DRTC, (DK20579), of Washington University. Preliminary data from some of the animals were presented in abstracts and published in meeting proceedings ( J Am Soc Nephrol 13:45A, 2002; Kidney Int 61:S23–S26, 2002). We wish to thank Curis, Inc. for the supply of BMP-7 used in the studies, and Dr. Kuber Sampath and Dr. John McCartney for valuable discussions and support of these efforts.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
AB - 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.
KW - BMP-7
KW - Chronic kidney disease
KW - Diabetic nephropathy
UR - http://www.scopus.com/inward/record.url?scp=0037648482&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2003.00035.x
DO - 10.1046/j.1523-1755.2003.00035.x
M3 - Article
C2 - 12753291
AN - SCOPUS:0037648482
SN - 0085-2538
VL - 63
SP - 2037
EP - 2049
JO - Kidney International
JF - Kidney International
IS - 6
ER -