TGF-β–Activated Kinase 1 Is Crucial in Podocyte Differentiation and Glomerular Capillary Formation

Abstract

TGF-b-activated kinase 1 (TAK1) is a key intermediate in signal transduction induced by TGF-b or inflammatory cytokines, such as TNF-a and IL-1, which are potent inducers of podocyte injury responses that lead to proteinuria and glomerulosclerosis. Nevertheless, little is known about the physiologic and pathologic roles of TAK1 in podocytes. To examine the in vivo role of TAK1, we generated podocyte-specific Tak1 knockout mice (Nphs2-Cre mice, Tak1 Δ/Δ mice exhibited impaired formation of podocyte foot processes that caused disruption of the podocyte architecture with prominent foot process effacement. Intriguingly, Tak1 Δ/Δ mice displayed increased expression of vascular endothelial growth factor within the glomerulus and abnormally enlarged glomerular capillaries. Furthermore, 4-and 7-week-old Tak1 Δ/Δ mice with proteinuria had increased collagen deposition in the mesangium and the adjacent tubulointerstitial area. Thus, loss of Tak1 in podocytes is associated with the development of proteinuria and glomerulosclerosis. Taken together, our data show that TAK1 regulates the expression of Wilms' tumor suppressor 1, nephrin, and vascular endothelial growth factor and that TAK1 signaling has a crucial role in podocyte differentiation and attainment of normal glomerular microvasculature during kidney development and glomerular filtration barrier homeostasis.

Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy

“…There is now evidence for ‘cross‐talk’ between podocytes and glomerular endothelial cells . We found that at 6 months after podocyte‐specific PTEN deletion, there was swelling of glomerular endothelial cells, followed by obliteration of some of the glomerular capillaries, suggesting that PTEN deletion in podocytes interrupts communication between podocytes and glomerular endothelial cells.…”

TGF-β signaling in the kidney: profibrotic and protective effects

“…Data from in vitro studies indicate that TGF-␤1-stimulated collagen expression in mesangial cells is mediated via the TAK1/MKK3/p38 signaling cascade and fibronectin expression in fibroblasts (13,38,69). Moreover, investigations using pharmacological and genetic blockade in in vivo models of glomerular and tubulointerstitial injury in mice have shown that the TAK1/MKK3/p38 and JNK pathways promote renal fibrosis (13,39). Both p38 and JNK are downstream targets of TAK1 activation.…”

Glomerular development – Shaping the multi-cellular filtration unit

“…Vegf-A expression in podocytes is in part dependent on the transcription factor LMX1B, leading to reduced VEGF production and decreased fenestration of endothelial cells in LMX1B deficient mice [57]. In contrast, the deletion of TGF-ˇ-activated kinase 1 (TAK1) in podocytes increases VEGF production causing abnormalities in glomerular and capillary formation [58]. Thus, the function of tightly balanced VEGF-A expression is indispensable for the development and maintenance of glomerular structure and function.…”