Editors' ChoiceChronic Kidney Disease

What’s at the “Foot” of Kidney Disease?

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Science Translational Medicine  07 Dec 2011:
Vol. 3, Issue 112, pp. 112ec199
DOI: 10.1126/scitranslmed.3003538

One of the early signs of chronic kidney disease (CKD), which afflicts about 17% of the US adult population, is the presence of excess protein in the urine (proteinuria). Urine formation begins at glomeruli—tufts of capillaries in the kidney—where blood is filtered so that electrolytes and some small molecules are excreted but proteins are retained in the blood. Kidney injury leads to reduced glomerular filtration and proteinuria. Important CKD risk factors include diabetes, hypertension, and vascular disease. Although their mechanisms of kidney injury are diverse, the key final common pathway is injury to the podocytes—cells with long foot processes that wrap around glomerular capillaries, leaving slits through which the blood is filtered. Molecularly, transforming growth factor–β1 (TGF-β1), a potent cytokine implicated in CKD, has been linked to podocyte dysfunction and proteinuria. In recent work, Wang et al. sought to clarify this connection.

The Wnt/β-catenin pathway regulates cell proliferation and differentiation and has also been implicated in CKD pathogenesis. The authors found that TGF-β1 markedly induced Wnt1 expression, β-catenin activation, and Wnt target gene expression in cultured mouse podocytes. This up-regulation requires intact TGF-β1 receptor and Wnt receptor signaling pathways. Furthermore, the authors established an elegant mouse model of CKD by means of intravenous injection of naked plasmid vectors encoding TGF-β1, which caused a reproducible increase of Wnt1 expression in the glomeruli and concomitant podocyte injury and proteinuria. In this model, TGF-β1–induced podocyte injury requires an intact Wnt/β-catenin pathway; expression of a natural Wnt antagonist, DKK1, abolishes β-catenin activation, inhibits downstream target expression, and more importantly, reduces proteinuria in vivo.

Although TGF-β1 and Wnt/β-catenin pathways have independently been identified as key factors in the progression of CKD, this report sheds light on how these two signaling pathways interact in podocytes. These pathways are essential for early glomerular development, yet their reactivation seems to interfere with the function of mature podocytes. This work is highly relevant to human CKD, because up-regulated TGF-β1 and Wnt expression has been associated with diabetic nephropathy and other common types of renal injury. Thus, genetic or pharmacological inhibition of Wnt/β-catenin signaling might ameliorate CKD and proteinuria. The future is bright for targeted CKD therapy.

D. Wang et al., Canonical Wnt/β-catenin signaling mediates transforming growth factor–β1-driven podocyte injury and proteinuria. Kidney Int. 80, 1159–1169 (2011). [Abstract]

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