BMP7: The Kidney’s Declining Repair Signal Draws New Therapeutic Attention

Bone morphogenetic protein 7, a member of the transforming growth factor-beta superfamily, has emerged as one of the most versatile protective signals in the kidney, according to a comprehensive review published in Cell Signaling, Inflammation & Disease. The review, authored by Heng Wang, Yaling Li, and Guoping Zheng and published on 17 June 2026, synthesizes evidence spanning embryonic development, adult renal physiology, and experimental kidney disease to argue that BMP7 operates as a multilayer regulatory network rather than a single linear pathway. The authors describe BMP7 as an endogenous renoprotective factor with anti-inflammatory, anti-fibrotic, and regenerative functions whose expression progressively declines with aging and chronic kidney injury, positioning its restoration as a promising but still incompletely understood therapeutic strategy.

The clinical context is substantial. More than 850 million people worldwide are affected by kidney diseases, including acute kidney injury, chronic kidney disease, and treated kidney failure, and these conditions can progress to end-stage kidney disease requiring kidney replacement therapy. Renal fibrosis, characterized by myofibroblast activation and excessive deposition of extracellular matrix, serves as the unifying hallmark and final common pathway of progressive kidney injury regardless of the initiating insult. Transforming growth factor-beta 1 has long been recognized as a central profibrotic cytokine driving this process, yet clinical trials of anti-TGF-β1 therapies have failed to show definitive efficacy despite significant benefits in preclinical models. The review attributes this failure to the pleiotropic nature of TGF-β1, which also performs critical anti-inflammatory and homeostatic roles in immune surveillance, cell proliferation, and wound healing, making global blockade problematic.

BMP7 offers an alternative approach because it counteracts the profibrotic effects of TGF-β1 throughout the entire signaling cascade, from receptor engagement to downstream signal transduction. During embryonic kidney development, BMP7 is indispensable for normal nephrogenesis. In mice lacking BMP7, severe developmental abnormalities arise in the kidneys, skeleton, and eyes, leading to death from renal failure within 24 hours after birth. Expression begins as early as embryonic day 7.5 in the surface ectoderm and notochord, and throughout kidney development between embryonic days 10.5 and 16.5, BMP7 is prominently expressed in both the metanephric ureteric bud and the metanephric mesenchyme, where it is required for ureteric bud branching morphogenesis and for maintaining mesenchymal cell survival and differentiation. Notably, BMP7 is the only BMP family member continuously expressed in both the metanephric mesenchyme and the adjacent ureteric epithelium throughout kidney development.

In the adult kidney, BMP7 expression becomes more spatially restricted than in the fetus, localizing predominantly to distal nephron segments including the ureteric epithelium, collecting ducts, thick ascending limbs, and distal convoluted tubules, as well as glomerular parietal epithelial cells and podocytes. Intriguingly, proximal tubular cells respond robustly to BMP7 both in vivo and in vitro but do not produce the ligand themselves; instead, they express BMP receptors type IA, IB, and II, indicating high ligand sensitivity without endogenous production. This arrangement suggests a paracrine signaling mode within the nephron in which proximal tubular cells function primarily as BMP7-responsive effector cells rather than a source of the protein. Multiple studies have demonstrated that BMP7 expression is markedly reduced across various kidney diseases, undermining its protective capacity precisely when it is most needed.

At the molecular level, BMP7 signals through both canonical and non-canonical pathways. In the canonical route, BMP7 binds type II receptors, which recruit and phosphorylate type I receptors including ACVR1, BMPR1A, and BMPR1B, forming a stable heterotetrameric complex that activates SMAD1/5/8. These SMADs associate with SMAD4 to form a transcriptional complex that translocates into the nucleus and regulates target gene expression, while the inhibitory SMAD6 competitively interferes with this interaction to attenuate signaling. Non-canonical signaling engages ERK and AKT pathways through receptor complexes composed of BMPR1A or ACVR1 together with ACVR2A or BMPR2, and BMP7 also regulates MAPK, PI3K/AKT, and AMPK/mTOR cascades. In unilateral ureteral obstruction-induced renal fibrosis, BMP7 specifically inhibited PI3K/AKT signaling while increasing PTEN expression, thereby attenuating TGF-β1-mediated profibrotic signaling and collagen deposition, whereas myeloid PTEN deficiency aggravated renal inflammation and fibrosis.

BMP7 activity is further controlled by an elaborate extracellular regulatory network. Positive modulators include Kielin-chordin-related protein, which directly binds BMP7 and increases its affinity for type I receptors, and membrane-bound SCUBE1, which acts as a BMP co-receptor and attenuates acute kidney injury in ischemia-reperfusion models. CD44v3 enhances BMP7 signaling through its heparan sulfate-binding domain, and insulin-like growth factor binding protein 3 cooperates with BMP7 to augment AKT phosphorylation and promote anti-apoptotic signaling in podocytes. Conversely, uterine sensitization-associated gene 1 is considered the most abundant endogenous BMP7 antagonist in the kidney, sequestering the ligand and exacerbating tubular injury in mouse models of acute kidney injury and unilateral ureteral obstruction. Additional antagonists including chordin, connective tissue growth factor, twisted gastrulation protein homolog 1, and gremlin 1 and 2 similarly inhibit BMP7 signaling through direct ligand binding. Post-transcriptional mechanisms add further layers, with microRNAs such as miR-384-5p, miR-22, and miR-135b suppressing BMP7 translation, and ubiquitin conjugation factor E4A promoting ubiquitin-mediated degradation of the protein.

The functional antagonism between BMP7 and TGF-β1 signaling appears central to determining whether injured kidneys progress toward fibrosis or repair. TGF-β1 predominantly activates SMAD2/3-dependent profibrotic pathways, whereas BMP7 activates SMAD1/5/8 signaling that promotes reparative and anti-fibrotic transcriptional programs. Experimental kidney injury models consistently demonstrate that loss of BMP7 activity is accompanied by enhanced TGF-β1 signaling and progressive fibrosis, while restoration of BMP7 partially reverses maladaptive tissue remodeling. Clinically, intrarenal BMP7 expression shows a progressive decline across all stages of chronic kidney disease compared with healthy controls, with a pronounced reduction in patients with stage III disease, and in renal allograft tissues, downregulation of BMP7 correlates with interstitial fibrosis and tubular atrophy. Mechanistically, renal overexpression of BMP7 activates Smad1/5/8 signaling while inhibiting TGF-β1-Smad3 signal transduction, reversing TGF-β1-induced epithelial-mesenchymal transition and matrix metalloproteinase-2 activation.

Beyond fibrosis, BMP7 exerts coordinated anti-inflammatory and regenerative effects. It directly inhibits interactions between proximal tubular epithelial cells and monocytes, reduces TGF-β1 production within proximal tubules, and alleviates renal inflammation by inhibiting oxidative stress and downregulating p38 and p44/42 MAPK pathways, which reduces expression of monocyte chemoattractant protein-1. BMP7 also appears to promote macrophage polarization toward M2-like phenotypes in several injury models, although the review cautions that the conventional M1/M2 classification may oversimplify macrophage heterogeneity in kidney diseases, since certain M2-associated populations can promote fibroblast activation and fibrotic progression. On the regenerative front, recombinant BMP7 administration suppressed apoptosis of tubular epithelial cells in acute kidney injury models, and in a mouse model of crescentic glomerulonephritis, systemic recombinant BMP7 reversed the phenotype of already activated fibroblasts, driving their conversion back to epithelial cells through mesenchymal to epithelial transition via SMAD1/5/8-dependent signaling. BMP7 has also been shown to reverse hypermethylation of the Rasal1 promoter through Tet3-mediated DNA hydroxymethylation, suppressing fibroblast activation and renal fibrosis progression through epigenetic mechanisms.

Translational efforts are advancing along two broad strategies: exogenous supplementation and endogenous restoration. In a diabetic rat model, intravenous recombinant BMP7 reversed diabetes-induced renal hypertrophy and normalized glomerular filtration rate, urinary albumin excretion, and glomerular histological architecture, though the short in vivo half-life of recombinant protein limits sustained efficacy. Engineered variants address this limitation; a glycosylated human BMP7 fused to human serum albumin exhibits an approximately tenfold longer plasma half-life than recombinant BMP7, and once-weekly administration markedly ameliorated renal fibrosis in mice with unilateral ureteral obstruction. Mesenchymal stem cell-derived exosomes containing BMP7-associated signaling components represent another delivery platform, although direct mechanistic evidence defining BMP7 as a dominant functional exosomal cargo remains limited. Endogenous activation strategies include clinically approved or investigational drugs such as finerenone, zaprinast, avanafil, liraglutide, and statins, herbal formulations including Huangqi decoction and Astragalus membranaceus, histone deacetylase inhibitors such as sulforaphane, and modulation of extracellular antagonists including USAG1 inhibition and KCP overexpression.

Despite encouraging preclinical findings, the review emphasizes that clinical translation remains limited. Current evidence is predominantly derived from in vitro systems and animal models, with direct clinical validation in humans still sparse. A search of ClinicalTrials.gov reveals that BMP7-based therapies are currently concentrated in orthopedic indications, and only one registered clinical trial directly related to kidney disease, entitled ACE Reno, Pico Cell Matrix and Its Effect on eGFR in Chronic Kidney Diseases, is currently recruiting; ACE Reno is an orally administered mucosal solution designed to mimic BMP7 activity through its peptide components. Major translational barriers include the short biological half-life and limited stability of recombinant BMP7, difficulties achieving kidney-specific delivery, and safety concerns around ectopic ossification and osteogenic adverse effects, which may be especially relevant in chronic kidney disease patients who frequently exhibit disturbed mineral metabolism and vascular calcification. The optimal therapeutic window, treatment duration, and patient selection criteria remain poorly defined, and the authors conclude that large-scale, well-designed clinical trials are still needed to determine the long-term efficacy, safety, and translational value of BMP7-targeted interventions in human kidney diseases.

Subject of Research: The multilayer regulatory roles of BMP7 signaling in kidney development, inflammation, fibrosis, and regeneration, and the challenges of translating BMP7-based therapies into clinical practice.

Article Title: BMP7 in kidney development and disease: a multilayer regulatory network integrating inflammation, fibrosis, and regeneration

Article References: Wang, H., Li, Y., & Zheng, G. (2026). BMP7 in kidney development and disease: a multilayer regulatory network integrating inflammation, fibrosis, and regeneration. Cell Signaling, Inflammation & Disease, 1(1), Article 2. https://doi.org/10.1186/s44505-026-00002-0

Image Credits: AI Generated

DOI: 10.1186/s44505-026-00002-0

Keywords: BMP7, kidney disease, renal fibrosis, TGF-β1, chronic kidney disease, acute kidney injury, SMAD signaling, renal regeneration, anti-inflammatory, drug delivery, clinical translation, nephrology