Pathophysiology of the Chronic Kidney Disease-Mineral Bone Disorder
Pathophysiology of the Chronic Kidney Disease-Mineral Bone Disorder
We, and several other investigators, have shown that kidney diseases reactivate developmental processes involved in nephrogenesis during disease stimulated renal repair. Among the nephrogenic factors reactivated in renal repair, the Wnt (portmanteau of Wingless and Integrated) family is critical for tubular epithelial reconstitution. In the control of Wnt function, canonical signaling transcriptionally induces the expression of a family of Wnt inhibitory proteins, which are secreted proteins that serve to restrict the extent of Wnt stimulation to autocrine or paracrine factors. The Wnt inhibitors are circulating factors, and the family includes the Dickkopfs (Dkk). We have shown that various forms of kidney disease increase renal expression of Wnt inhibitors and increase their levels in the circulation.
Neutralizing a key Wnt inhibitor elevated in the circulation in CKD, Dkk1, inhibited CKD induced vascular dedifferentiation, vascular calcification, and renal osteodystrophy. This effect was surprising as Wnt signaling in the vascular smooth muscle is implicated in stimulating osteoblastic transition and vascular calcification. However, recent studies demonstrate that Dkk1-mediated inhibition of aortic Wnt7b stimulates smad-mediated aortic endothelial-mesenchymal transition (EndMT) and vascular calcification. EndMT is a developmental physiologic process involved in the development of the cardiac valves, the cardiac septum and the aortic root, and it may or may not contribute to cardiac fibrosis in various adult disease states. As EndMT is a process driven by smad transcription factors activated by factors in the transforming growth factor β (TGFβ) superfamily, we investigated whether other factors involved in attempted renal repair during kidney disease derive from the TGFβ superfamily and are increased in the circulation during CKD. Of the TGFβ superfamily members, activin, a known renal developmental factor and circulating hormone, was the primary candidate.
Activin is increased in the circulation by CKD associated with increased expression of activin in the kidney. Surprisingly, the activin type 2A receptor (ActRIIA) was decreased by CKD in the aortic vascular smooth muscle and not the endothelium. We demonstrated that inhibiting activin signaling using an activin ligand trap blocked CKD-stimulated vascular smooth muscle osteoblastic transition, vascular calcification, and inhibited renal fibrosis. We found that inhibiting activin signaling decreased renal Wnt activation and circulating Dkk1. As a result a composite vascular effect of indirectly increasing endothelial Wnt signaling through loss of Dkk1 in the circulation, and decreased vascular smooth muscle Wnt activation by blocking direct activin vascular smooth muscle cells effects was produced by the ActRIIA ligand trap.
Discoveries in the Pathogenesis of the Chronic Kidney Disease – Mineral Bone Disorder
We, and several other investigators, have shown that kidney diseases reactivate developmental processes involved in nephrogenesis during disease stimulated renal repair. Among the nephrogenic factors reactivated in renal repair, the Wnt (portmanteau of Wingless and Integrated) family is critical for tubular epithelial reconstitution. In the control of Wnt function, canonical signaling transcriptionally induces the expression of a family of Wnt inhibitory proteins, which are secreted proteins that serve to restrict the extent of Wnt stimulation to autocrine or paracrine factors. The Wnt inhibitors are circulating factors, and the family includes the Dickkopfs (Dkk). We have shown that various forms of kidney disease increase renal expression of Wnt inhibitors and increase their levels in the circulation.
Neutralizing a key Wnt inhibitor elevated in the circulation in CKD, Dkk1, inhibited CKD induced vascular dedifferentiation, vascular calcification, and renal osteodystrophy. This effect was surprising as Wnt signaling in the vascular smooth muscle is implicated in stimulating osteoblastic transition and vascular calcification. However, recent studies demonstrate that Dkk1-mediated inhibition of aortic Wnt7b stimulates smad-mediated aortic endothelial-mesenchymal transition (EndMT) and vascular calcification. EndMT is a developmental physiologic process involved in the development of the cardiac valves, the cardiac septum and the aortic root, and it may or may not contribute to cardiac fibrosis in various adult disease states. As EndMT is a process driven by smad transcription factors activated by factors in the transforming growth factor β (TGFβ) superfamily, we investigated whether other factors involved in attempted renal repair during kidney disease derive from the TGFβ superfamily and are increased in the circulation during CKD. Of the TGFβ superfamily members, activin, a known renal developmental factor and circulating hormone, was the primary candidate.
Activin is increased in the circulation by CKD associated with increased expression of activin in the kidney. Surprisingly, the activin type 2A receptor (ActRIIA) was decreased by CKD in the aortic vascular smooth muscle and not the endothelium. We demonstrated that inhibiting activin signaling using an activin ligand trap blocked CKD-stimulated vascular smooth muscle osteoblastic transition, vascular calcification, and inhibited renal fibrosis. We found that inhibiting activin signaling decreased renal Wnt activation and circulating Dkk1. As a result a composite vascular effect of indirectly increasing endothelial Wnt signaling through loss of Dkk1 in the circulation, and decreased vascular smooth muscle Wnt activation by blocking direct activin vascular smooth muscle cells effects was produced by the ActRIIA ligand trap.
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