Bramlage, Carsten P.; Tampe, Bjoern; Koziolek, Michael; Maatouk, Imad; Bevanda, Jelena; Bramlage, Peter; Ahrens, Katharina; Lange, Katharina; Schmid, Holger; Cohen, Clemens D.; Kretzler, Matthias; Mueller, Gerhard A.:
Bone Morphogenetic Protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis.
In: BMC Nephrology
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.