Ramping up endogenous defences against chronic kidney disease

Bone morphogenic proteins (BMPs) are a group of glycoproteins that belong to the transforming growth factor beta superfamily. Of the several members expressed in the kidney, BMP-7 (known also as osteogenic protein-1) is of particular interest to nephrologists due to its critical role in branching morphogenesis during renal development and its ability to preserve tubular epithelial cell phenotype in the face of adversity, at least in experimental models [1]. The BMP-7 null mice die in the neonatal period in renal failure due to hypoplastic kidneys [2,3]. Even in the post-natal period, the distal tubules and collecting ducts continue to be a major site of BMP-7 synthesis [4]. Reduced expression has been reported in several renal diseases including ischaemic nephropathy, diabetic nephropathy, cyclosporine nephrotoxicity and 5/6 nephrectomy [5–9]. Intervention studies with recombinant BMP-7 first demonstrated salutary effects in animal models of acute renal failure and were followed by reports of reduced fibrosis in several chronic kidney disease models [9–14]. Although its renoprotective mechanisms of action are not fully elucidated, receptor-dependent effects on proximal tubular epithelium appear to be particularly important [12]. The BMP-7 transmits extracellular signals to nuclei by binding to BMP type II receptors (BMPR II) or the activin type II receptors (ActRIIa or ActRIIb) in conjunction with type I receptors [activin receptor-like kinase-2 (Alk2), Alk3 or Alk6], followed by activation of Smads 1, 5 and 8 and/or members of the mitogenactivated protein kinase family [15–17]. During renal injury, BMP-7 antagonizes transformation of renal tubular epithelial cell into fibroblast-like mesenchymal cells that are characterized by de novo synthesis of fibrillar collagens and enhanced overall matrix protein production (the process of epithelial-tomesenchymal transition (EMI)). In experimental studies, these transformed cells can be identified phenotypically as cells that have lost E-cadherin and acquired a-smooth muscle actin (SMA) and/or fibroblast specific protein-1 (protein S100A4). When tubular basement membranes are degraded by proteases, such matrix metalloproteinases surviving transformed cells may take up residence in the interstitial space as activated (myo)fibroblasts and participate in scar formation. For unknown reasons, interstitial myofibroblasts appear to have other cellular origins, including resident interstitial fibroblasts or bone marrow-derived precursors and, at present, the relative contribution of the BMP-7-inhibitable EMT process remains controversial [18]. A particularly exciting finding is the potential for BMP-7 to reverse the EMT process, converting transdifferentiated mesenchyme-like tubular epithelium back to mature epithelial cells [19]. Achieving this effect in humans with chronic kidney disease could theoretically lay the groundwork to reverse fibrosis. The BMP-7 has been ascribed other biological functions that may also confer renoprotection, including significant anti-inflammatory effects [20,21]. Whether BMP-7 therapeutics will ever become a reality for human chronic kidney disease is unknown at this time. In addition to recombinant protein design and production challenges, there are other theoretical issues of concern. First, BMP-7 is a relatively small homodimeric peptide ( 35 kDa) that is likely to be filtered in proteinuric renal diseases. Although not protective in a model of overload proteinuria possibly for this reason, BMP-7 did improve several parameters of renal injury in mouse models of Alport syndrome, anti-GBM nephritis and lupus nephritis [12,13,22]. Second, although BMP-7 receptors are expressed within the cortex (podocytes and proximal convoluted tubules) and medullary collecting ducts of normal rodents, little is known about receptor expression patterns in human renal diseases [23]. Third, given the relatively high endogenous levels of renal BMP-7, it stands to reason that exogenous BMP-7 would be Correspondence and offprint requests to: Dr Allison A. Eddy, The Children’s Hospital and Regional Medical Center, Division of Nephrology, Mail Stop M1-5, 4800 Sand Point Way NE, Seattle, WA 98105, USA. Email: allison.eddy@seattlechildrens.org