Bone morphogenetic protein signaling in the developing kidney: present and future

Cain, Jason; Hartwig, Sunny; Bertram, John F.; Rosenblum, Norman D.

doi:10.1111/j.1432-0436.2008.00265.x

Cited by 38 publications

(45 citation statements)

References 102 publications

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“…In this work we show that Irx proteins act as activators during kidney formation. Thus, one possible mechanism of action of Irx proteins could be to 3205 RESEARCH ARTICLE Irx genes in Xenopus kidney development upregulate Bmp signalling, which is known to participate at many steps during vertebrate kidney formation (Cain et al, 2008). Consistent with this idea, the reduction of Bmp signalling during Xenopus neurula stages causes defects similar to those produced by Irx gene impairment (Bracken et al, 2008).…”

Section: Discussionsupporting

confidence: 58%

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A dual requirement for Iroquois genes duringXenopuskidney development

et al. 2008

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Section: Discussionsupporting

confidence: 58%

“…The Bmp pathway is implicated at several steps during vertebrate kidney development (Cain et al, 2008). A recent report showed that blocking this pathway during Xenopus neurula stages impaired pronephros formation (Bracken et al, 2008).…”

Section: Rescue Of Irx-dependent Kidney Defects By Increasing Bmp Sigmentioning

confidence: 99%

A dual requirement for Iroquois genes duringXenopuskidney development

et al. 2008

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“…to mesenchymal survival (36). Finally, the downstream target of BMP4 is Smad1 in mesangial cells, as demonstrated in the present study, whereas the downstream target of BMP7 in mesangial cells is Smad5 (37).…”

Section: Discussionsupporting

confidence: 50%

Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy

et al. 2015

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Diabetic nephropathy is the leading cause of end-stage renal disease. It is pathologically characterized by the accumulation of extracellular matrix in the mesangium, of which the main component is a1/a2 type IV collagen (Col4a1/a2). Recently, we identified Smad1 as a direct regulator of Col4a1/a2 under diabetic conditions in vitro. Here, we demonstrate that Smad1 plays a key role in diabetic nephropathy through bone morphogenetic protein 4 (BMP4) in vivo. Smad1-overexpressing mice (Smad1-Tg) were established, and diabetes was induced by streptozotocin. Nondiabetic Smad1-Tg did not exhibit histological changes in the kidney; however, the induction of diabetes resulted in an ∼1.5-fold greater mesangial expansion, consistent with an increase in glomerular phosphorylated Smad1. To address regulatory factors of Smad1, we determined that BMP4 and its receptor are increased in diabetic glomeruli and that diabetic Smad1-Tg and wild-type mice treated with a BMP4-neutralizing antibody exhibit decreased Smad1 phosphorylation and ∼40% less mesangial expansion than those treated with control IgG. Furthermore, heterozygous Smad1 knockout mice exhibit attenuated mesangial expansion in the diabetic condition. The data indicate that BMP4/Smad1 signaling is a critical cascade for the progression of mesangial expansion and that blocking this signal could be a novel therapeutic strategy for diabetic nephropathy.Diabetic nephropathy is a life-threatening complication of diabetes and the leading cause of end-stage renal disease (1). The structural features of diabetic nephropathy include thickening of the glomerular basement membrane (GBM) and mesangial matrix expansion (2,3). Mesangial matrix expansion is pathologically important because it leads to glomerulosclerosis accompanied by various tubulointerstitial damages and subsequent nephron loss (4,5). In addition, the severity of mesangial matrix expansion is clinically important because it is closely associated with the decline of the glomerular filtration rate (6).Mesangial matrix expansion is characterized by increased amounts of extracellular matrix (7), particularly a1/a2 type IV collagen (Col4a1/a2) (8). Although various peptides or growth factors are shown to mediate the regulation of this key component, the protein responsible for its direct regulation remains to be determined.Because various injuries of epithelial, endothelial, and mesangial cells converge on the accumulation of Col4a1/a2 in the mesangium, mesangial cells presumably play a central role for the regulation of Col4a1/a2, even if they are not the primary target of injury (9). Therefore, we attempted to elucidate the direct regulation of Col4a1/a2 under diabetic conditions and demonstrate that Smad1 can transcriptionally regulate Col4a1/a2 in the presence of advanced glycation end products in mesangial cells (10).Smad1 is an intracellular molecule originally cloned as a signal transducer of the transforming growth factor (TGF)-b superfamily (11). In response to these stimuli, Smad1 is phosphorylated at the COOH...

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“…This growth factor may act in an contexts and microenvironments (5,24,26,32). BMPs are expressed in the early developing kidney (5,20) and in the adult kidney, particularly during repair processes, since it is known that regenerative processes recapitulate embryonal development (3,7,25).…”

Section: Discussionmentioning

confidence: 99%

BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation

Simone

Cosola

Loverre

et al. 2012

American Journal of Physiology-Renal Physiology

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Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced α-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, α-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H2O2) induced α-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage.

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Bone morphogenetic protein signaling in the developing kidney: present and future

Cited by 38 publications

References 102 publications

A dual requirement for Iroquois genes duringXenopuskidney development

A dual requirement for Iroquois genes duringXenopuskidney development

Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy

BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation

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