Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN

Abstract

Diabetic nephropathy is characterized early in its course by glomerular hypertrophy and, importantly, mesangial hypertrophy, which correlate with eventual glomerulosclerosis. The mechanism of hypertrophy, however, is not known. Gene disruption of the tumor suppressor PTEN, a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway, in fruit flies and mice demonstrated its role in size control in a cell-specific manner. Here, we investigated the mechanism of mesangial hypertrophy in response to high extracellular glucose. We link early renal hypertrophy with significant reduction in PTEN expression in the streptozotocin-induced diabetic kidney cortex and glomeruli, concomitant with activation of Akt. Similarly, exposure of mesangial cells to high concentrations of glucose also decreased PTEN expression and its phosphatase activity, resulting in increased Akt activity. Expression of PTEN inhibited high-glucose-induced mesangial cell hypertrophy, and expression of dominant-negative PTEN was sufficient to induce hypertrophy. In diabetic nephropathy, the hypertrophic effect of hyperglycemia is thought to be mediated by transforming growth factor-␤ (TGF-␤). TGF-␤ significantly reduced PTEN expression in mesangial cells, with a reduction in its phosphatase activity and an increase in Akt activation. PTEN and dominant-negative Akt attenuated TGF-␤-induced hypertrophy of mesangial cells. Finally, we show that inhibition of TGF-␤ signal transduction blocks the effect of high glucose on PTEN downregulation. These data identify a novel mechanism placing PTEN as a key regulator of diabetic mesangial hypertrophy involving TGF-␤ signaling. Diabetes 55: [2115][2116][2117][2118][2119][2120][2121][2122][2123][2124][2125] 2006

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…In line with this, we also demonstrated that high glucose and TGF-␤ 1 activated Akt, downstream of PI3 kinase. Additionally, previous reports have described PI3 kinase and Akt activation by high glucose in mesangial cells and kidneys from streptozotocin-induced diabetes and identified a role for Akt in ECM production (30,46,61). High glucose-induced TGF-␤ 1 signal transduction may increase PI3 kinase by transactivating the EGF receptor (see above) and by downregulating the lipid phosphatase and PI3 kinase-negative regulator 3Ј-phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (30).…”

“…PI3 kinase phosphorylates the D-3 position of the inositol ring of phosphoinositides, recruiting proteins with pleckstrin homology domains to membranes, such as PKB/kt and PKC-/ . TGF-␤ 1 is reported to stimulate PI3 kinase in mesangial cells (14,30,46) and fibroblasts (6,37,60). We previously reported that primary cultured rat mesangial cells express predominantly PKC-with little or undetectable PKC-.…”

FOG2 Protein Down-regulation by Transforming Growth Factor-β1-induced MicroRNA-200b/c Leads to Akt Kinase Activation and Glomerular Mesangial Hypertrophy Related to Diabetic Nephropathy

“…However, the PI3K-Akt pathway has also been implicated in mediating the cellular effects of TGF-␤ in DN (15,17,18). Reports show that the PI3K-Akt signaling cascade triggered by TGF-␤ induces glomerular mesangial and renal tubular hypertrophy, important pathologic phenotypic changes in the course of DN progression (16,41). Because of its well known role as a signal transducer of TGF-␤ in DN, the mechanisms by which TGF-␤ activates Akt has elicited much interest.…”

“…Therefore, TGF-␤ is a critical medi-ator of the effects of high glucose in models of DN. Recent studies have found that PI3K-Akt activation by TGF-␤ plays a key role in its downstream actions (15)(16)(17)(18). Interestingly, recent studies have shown that down-regulation of phosphatase and tensin homolog (PTEN) is a key mechanism by which TGF-␤ activates PI3K-Akt and that this occurs via microRNAs (miRNAs) such as miR-216a/miR-217 that target PTEN (16,19).…”

“…Previous studies have shown that glomerular mesangial hypertrophy, a major feature of DN, is a downstream consequence of Akt activation (16,19). We next tested whether the increase in Akt phosphorylation ensued by FOG2 knockdown also results in increased cellular hypertrophy in MMC.…”