PTEN Regulates Renal Extracellular Matrix Deposit via Increased CTGF in Diabetes Mellitus

Abstract

Extracellular matrix accumulation and fibrosis are the features of diabetic nephropathy. PI3K (phosphatidylinositol 3-kinase)/Akt (protein kinase B) signal pathway and its inhibitor PTEN (phosphatase and tensin homolog deleted on chromosome 10) are revealed to modulate renal fibrosis. However, the exact mechanism is still not well known. In the present study we found that compared with normal mice, diabetic mice showed decreased PTEN, increased phospho-Akt (Ser 473), phospho-Akt (Thr 308), CTGF (connective tissue growth factor), α-SMA (α-smooth muscle actin), and matricellular protein in kidney. Knocking down of PTEN caused an increase in phospho-Akt (Ser 473), phospho-Akt (Thr 308), CTGF, secreted fibronectin, and secreted Col 3 in HKC cells (human renal tubular epithelial cells). Again, in vitro experiment revealed 1.89, 2.18, 1.92, 3.06, 2.06-fold increases of phospho-Akt (Ser 473), phospho-Akt (Thr 308), CTGF, secreted fibronectin, and secreted Col 3 in high glucose-stimulated HKC cells in comparison with normal control cells. Furthermore, knocking down of CTGF reversed increased secreted fibronectin and Col 3 in high glucose-treated HKC cells. Moreover, transfection of PTEN expression vector prevented high glucose-caused these changes in HKC cells. Especially, CTGF expression, secretion of fibronectin and Col 3 were, respectively, decreased by 38.81, 53.85, and 39.12%. The treatment of LY294002 inhibited phospho-Akt (Ser 473) and phospho-Akt (Thr 308) expression followed by decreased CTGF, secretory fibronectin and secretory Col 3 in high glucose-treated HKC cells. In the end our study suggests that PTEN regulates renal extracellular matrix production via activated Akt and increased CTGF in diabetes mellitus.

The Small Tellurium Compound AS101 Ameliorates Rat Crescentic Glomerulonephritis: Association with Inhibition of Macrophage Caspase-1 Activity via Very Late Antigen-4 Inactivation

“…Monocytes are involved not only in acute inflammation but also in glomerulosclerosis, a feature common to both immune and non-immune forms of progressive renal disease (40). Collectively, these data are in line with reports showing increased MCP-1 production and FN accumulation by CTGF (41, 42). …”

Src Homology 2 Domain-Containing Inositol 5′-Phosphatase Ameliorates High Glucose-Induced Extracellular Matrix Deposition via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Renal Tubular Epithelial Cells

“…PI (3,4,5) P3 initiates a variety of signaling cascades by interacting with pleckstrin homology (PH) domain-containing proteins, most notably the serine kinase Akt [Vanhaesebroeck et al, 2010]. Similarly, in a previous study, we also demonstrated that the PI3K/Akt pathway was activated, including the full phosphorylation of Akt at Thr 308 and Ser 473, to increase the level of transforming growth factor-b1 (TGF-b1) protein and ECM accumulation in high glucose-treated renal tubular cells [Zhu et al, 2016]. Therefore, approaches to inhibit the activation of the PI3K/Akt pathway may become therapeutic points to prevent renal injuries from diabetes mellitus.…”

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

“…Previous studies showed a relationship between the PTEN/Akt pathway and heart fibrosis [36]. Some evidence directly illustrated that PTEN regulated renal fibrosis during diabetes mellitus [37]. At present, there are few studies regarding PTEN involvement in AKI-induced renal fibrosis.…”