Vitamin C deficiency exacerbates diabetic glomerular injury through activation of transforming growth factor-β signaling.

Abstract

BACKGROUND:

The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (VC) in diabetic humans and experimentally diabetic animals. Herein, we access the effects of VC deficiency on the diabetic kidney injury and explore the underlying mechanism.

METHODS:

l-gulonolactone oxidase conventional knockout (Gulo-/-) mice genetically unable to synthesize VC were subjected to streptozotocin-induced diabetic kidney injury and the role of VC deficiency was evaluated by biochemical and histological approaches. Rat mesangial cells were cultured to investigate the underlying mechanism.

RESULTS:

Functionally, VC deficiency aggravates the streptozotocin-induced renal insufficiency, exhibiting the increased urine albumin, water intake, and urine volume in Gulo-/- mice. Morphologically, VC deficiency exacerbates the streptozotocin-induced kidney injury, exhibiting the increased glomerular expansion, deposition of Periodic Acid-Schiff- and Masson-positive materials, and expression of α-smooth muscle actin, fibronectin and type 4 collagen in glomeruli of Gulo-/- mice. Mechanistically, VC activates protein kinase B (Akt) to destabilize Ski and thereby induce the expression of Smad7, resulting in suppression of TGF-β/Smad signaling and extracellular matrix deposition in mesangial cells.

CONCLUSIONS:

VC is essential for the renal function maintenance in diabetes.

GENERAL SIGNIFICANCE:

Compensation for the loss of VC could be an effective remedy for diabetic kidney injury.

• Authors: Xing Ji, Xinhua Hu, Chaochun Zou, Hongfeng Ruan, Xueying Fan, Chao Tang, Wei Shi, Liu Mei, Haibin Zhu, Musaddique Hussain, Linghui Zeng, Xiaodong Zhang, Ximei Wu
• Journal: Biochimica et biophysica acta. General subjects (Biochim Biophys Acta Gen Subj) Vol. 1861 Issue 9 Pg. 2186-2195 (Sep 2017) ISSN: 0304-4165 [Print] Netherlands
• PMID: 28652077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Proto-Oncogene Proteins
• Ski protein, mouse
• Smad Proteins
• Transforming Growth Factor beta
• Streptozocin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Ascorbic Acid Deficiency (complications)
• Cells, Cultured
• DNA-Binding Proteins (genetics)
• Diabetes Mellitus, Experimental (complications)
• Diabetic Nephropathies (etiology)
• Extracellular Matrix (metabolism)
• Kidney Glomerulus (pathology)
• Mice
• Mice, Inbred C57BL
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins c-akt (physiology)
• Rats
• Signal Transduction (physiology)
• Smad Proteins (physiology)
• Streptozocin
• Transforming Growth Factor beta (physiology)