Indoxyl sulfate-induced activation of (pro)renin receptor is involved in expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells.

Abstract

Activation of (pro)renin receptor (PRR) is involved in the progression of chronic kidney disease. However, the role of indoxyl sulfate, a uremic toxin, in the activation of PRR is not clear. The present study aimed to clarify the role of indoxyl sulfate in activation of PRR, in relation to renal expression of fibrotic genes. Renal expression of PRR and renin/prorenin was up-regulated in chronic kidney disease rats compared with normal rats, whereas AST-120 suppressed these expression by reducing serum levels of indoxyl sulfate. Furthermore, administration of indoxyl sulfate to normotensive and hypertensive rats increased renal expression of PRR and renin/prorenin. Indoxyl sulfate induced expression of PRR and prorenin in cultured human proximal tubular cells (HK-2 cells). Indoxyl sulfate-induced PRR expression was inhibited by small interfering RNAs of signal transducer and activator of transcription 3 (Stat3) and nuclear factor-κB p65 in proximal tubular cells. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed indoxyl sulfate-induced PRR expression in proximal tubular cells. N-acetylcysteine prevented indoxyl sulfate-induced phosphorylation of Stat3 in proximal tubular cells. PRR small interfering RNA inhibited indoxyl sulfate-induced expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Taken together, indoxyl sulfate-induced up-regulation of prorenin expression and activation of PRR through production of reactive oxygen species and activation of Stat3 and nuclear factor-κB play an important role in the expression of TGF-β1 and α-smooth muscle actin in proximal tubular cells. Thus, indoxyl sulfate-induced activation of prorenin/PRR might be involved in renal fibrosis.

• Authors: Shinichi Saito, Hidehisa Shimizu, Maimaiti Yisireyili, Fuyuhiko Nishijima, Atsushi Enomoto, Toshimitsu Niwa
• Journal: Endocrinology (Endocrinology) Vol. 155 Issue 5 Pg. 1899-907 (May 2014) ISSN: 1945-7170 [Electronic] United States
• PMID: 24601883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Chelating Agents
• Oxides
• Reactive Oxygen Species
• Receptors, Cell Surface
• STAT3 Transcription Factor
• Stat3 protein, rat
• Tgfb1 protein, rat
• Transforming Growth Factor beta1
• smooth muscle actin, rat
• Carbon
• AST 120
• Indican
• Prorenin Receptor

Topics

• Actins (genetics, metabolism)
• Animals
• Carbon (therapeutic use)
• Cell Line
• Chelating Agents (therapeutic use)
• Disease Models, Animal
• Fibrosis
• Humans
• Hypertension, Renal (chemically induced, metabolism, pathology)
• Indican (adverse effects, antagonists & inhibitors, blood)
• Kidney Tubules, Proximal (drug effects, metabolism, pathology)
• Male
• Oxides (therapeutic use)
• RNA Interference
• Random Allocation
• Rats
• Rats, Inbred Dahl
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Receptors, Cell Surface (antagonists & inhibitors, genetics, metabolism)
• Renal Insufficiency, Chronic (chemically induced, drug therapy, metabolism, pathology)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Up-Regulation (drug effects)
• Prorenin Receptor