Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

Abstract

Stimulation of the bone morphogenetic protein (BMP) pathway protects the kidney from acute and chronic injury. Numerous regulators in the kidney control BMP signaling, offering many targets for therapeutic manipulation. Here, we screened for modulators of BMP signaling in the ischemia-sensitive S3 segment and found that Chordin-like 1 is expressed in this segment of both the mouse and human nephron. Chordin-like 1 specifically antagonizes BMP7, which is expressed in the neighboring distal nephron, and this depends on the presence of the protein Twisted gastrulation. Upon ischemia-induced degeneration of the S3 segment, we observed a reduction in Chordin-like 1 expression coincident with intense BMP signaling in tubules of the recovering kidney. Restored expression accompanied proximal tubule epithelia redifferentiation, again coincident with decreased BMP signaling. We propose that Chordin-like 1 reduces BMP7 signaling in healthy proximal tubules, and the loss of this activity upon sloughing of injured epithelia promotes BMP7 signaling in repopulating, dedifferentiated epithelia. As regenerating epithelia differentiate, Chordin-like 1 is again expressed, antagonizing BMP7. These data suggest a mechanism for dynamic regulation of renoprotective BMP7 signaling in the S3 segment of the proximal tubule.

Kidney Regeneration: Lessons from Development

“…In adult, BMP7 expression in the kidney is reduced after IR-AKI 18, 94 , and while the function and cellular origin BMP7 expression during post-AKI injury and repair are unknown, systemic treatment with BMP7, or the BMP7 mimetic THR-123, reduces tubular injury after IR-AKI 95, 96 . There is added complexity to this pathway since expression of the secreted selective BMP7 antagonist, Chordin-like 1, is also down-regulated in injured proximal tubular epithelial cells after IR-AKI, and this is associated with increased BMP-dependent Smad signaling in regenerating epithelial cells 97 . In the TRAP dataset, BMP4 and 7-expression were both increased in endothelial cells 24 hours after IR-AKI (Table 2), but there was no change in expression of either ligand, or the BMP antagonist Gremlin, in any of the other cell types.…”

Acute Kidney Injury in Older Adults

“…Chordin 1-regulated expression of bone morphogenic protein 7 also plays a role in restoring tubular epithelia after AKI. 97 More study is needed to determine whether senescent cells in the aging kidney undergo accelerated cell death or impair injury response. 90 It is possible that fewer tubular epithelial cells are available to de-differentiate and proliferate in response to injury, 41,98 hindering repair and decreasing the likelihood of recovery from AKI.…”

Effect of Chordin-Like 1 on MC3T3-E1 and Human Mesenchymal Stem Cells

“…However, the binding affinities of chordin-like 1 to the different BMP family members warrants further research. Moreover, the regulation of members of the BMP family is far from trivial with some members being able to antagonize or amplify the signal depending on their interaction with other members of the BMP family [Larrain et al, 2000;Gazzerro and Canalis, 2006;Larman et al, 2009;Moreno-Miralles et al, 2009].…”