Bone Morphogenetic Protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis

Background: 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. Methods: 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-beta induced
epithelial-to-mesenchymal transition (EMT), expression of TGF-beta
receptor type I (TGF-beta RI) and phosphorylated Smad 2 (pSmad 2)
as well as on TNF-alpha induced apoptosis of proximal tubular
cells. Results: 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-alpha-induced apoptosis and TGF-beta-induced EMT in human
proximal tubule cells possibly due to a decreased expression of
TGF-beta RI. In addition, BMP-7 was able to reverse
TGF-beta-induced phosphorylation of Smad 2. Conclusions: The
findings suggest a protective role for BMP-7 by counteracting the
TGF-beta and TNF-alpha-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.