Bone Morphogenetic Protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis
1 Department of Medicine, Nephrology and Rheumatology, Georg-August-University Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
2 Institute for Cardiovascular Pharmacology and Epidemiology, Menzelstrasse 21, 15831 Mahlow, Germany
3 Department of Medical Statistics, Georg-August-University Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
4 Department of Nephrology, Medical Policlinic, Ludwig Maximilians University Munich, Pettenkoferstr. 8a, D - 80336 Munich, Germany
5 Division of Nephrology and Institute of Physiology, University Zürich, Rämistr. 100, 8091 Zürich, Switzerland
6 Internal Medicine - Nephrology, University of Michigan, 1150 W. Medical Centre, Ann Arbor, USA
BMC Nephrology 2010, 11:31 doi:10.1186/1471-2369-11-31Published: 16 November 2010
Bone Morphogenetic Protein (BMP)-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described.
BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT)-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8) expression was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-β induced epithelial-to-mesenchymal transition (EMT), expression of TGF-β receptor type I (TGF-βRI) and phosphorylated Smad 2 (pSmad 2) as well as on TNF-α induced apoptosis of proximal tubular cells.
BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml) were able to reverse TNF-α-induced apoptosis and TGF-β-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-βRI. In addition, BMP-7 was able to reverse TGF-β-induced phosphorylation of Smad 2.
The findings suggest a protective role for BMP-7 by counteracting the TGF-β and TNF-α-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease.