Mesangial cell hypertrophy by high glucose is mediated by downregulation of the tumor suppressor PTEN

Lenin Mahimainathan, Falguni Das, Balachandar Venkatesan, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

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-β (TGF-β). TGF-β 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-β-induced hypertrophy of mesangial cells. Finally, we show that inhibition of TGF-β 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-β signaling.

Original languageEnglish (US)
Pages (from-to)2115-2125
Number of pages11
JournalDiabetes
Volume55
Issue number7
DOIs
StatePublished - Jul 2006

Keywords

  • HA, hemagglutinin
  • PDGF, platelet-derived growth factor
  • PI, phosphatidylinositol
  • PIP, PI 3,4,5-trisphosphate
  • TGF-β, transforming growth factor-β

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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