Abstract
Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.
Highlights
Podocytes have recently emerged as an early injury site in many types of kidney disease
Twsg1 functions as anti- and pro-Bmp factor: Twsg1 shows pro-Bmp activity enhanced by Crossveinless2 (Cv2) during kidney development[45], whereas Twsg1 inhibits Bmp signaling together with Chordin-like 1 (Chrdl1) in tubular epithelial cells of adult kidney[46]
We demonstrated that the administration of bone morphogenetic protein 7 (Bmp7) induces the differentiation and inhibits the proliferation of podocytes, whereas the simultaneous administration of Twsg1 antagonizes these effects of Bmp7
Summary
Podocytes have recently emerged as an early injury site in many types of kidney disease. The development of therapeutic techniques attenuating podocyte injury is expected to retard the progression of kidney disease. Bone morphogenetic protein 7 (Bmp7) is a member of the Bmp family within the TGF-b superfamily, and plays pivotal roles in the development of the kidneys and eyes[8,9]. While Bmp is widely expressed during development, its expression in most tissues decreases after birth, and the kidney becomes the main site of Bmp production among adult tissues. Bmp is highly expressed in podocytes, distal tubules, and collecting ducts[10], whereas native Bmp signaling in the healthy kidney occurs mainly in podocytes and collecting ducts[11]
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