Abstract
High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.
Highlights
The origin of circulating endotoxins in patients with diabetes is not yet fully known
The central role of the phosphoinositide 3-kinase (PI3K)dependent Akt signaling pathway in the regulation of cell survival raises the molecules that modulate its activity to key roles in regulating apoptosis in podocytes. 3-Phosphoinositidedependent protein kinase-1 (PDK1) is a 63-kDa serine/ threonine kinase that functions downstream of PI3K but upstream of Akt and serves as a major regulatory point in Akt signaling.[11]
In support of these observations, we have found that the incidence of bacterial infections correlates with the severity of diabetic nephropathy in Finnish patients with T1D.2
Summary
The origin of circulating endotoxins in patients with diabetes is not yet fully known. In addition to severe bacterial infections,[2] underlying systemic diseases (e.g., periodontitis) and life-style related factors (e.g., high-fat diet) may increase plasma levels of endotoxins in humans.[3,4,5] Interestingly, LPS in the sera of septic patients has previously been shown to induce apoptosis of kidney cells,[6] but the mechanism is not known. The central role of the phosphoinositide 3-kinase (PI3K)dependent Akt signaling pathway in the regulation of cell survival raises the molecules that modulate its activity to key roles in regulating apoptosis in podocytes. We hypothesized that PDK1, the key regulator of the PI3K/ Akt-mediated cell survival pathway, could have a role in regulating podocyte apoptosis, and that high LPS activity could downregulate PDK1, inducing apoptosis and podocyte injury
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