Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction
| Autor: | Didier Portilla, Shenyang Li, Peter M. Price, Judit Megyesi, Brian Shank, Krishnaswamy Kannan, Sue Theus, Jeremy S. Duffield, Nithya Mariappan |
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| Rok vydání: | 2013 |
| Předmět: |
Collagen Type IV
medicine.medical_specialty Physiology Down-Regulation Inflammation Mice Transgenic Collagen Type I Proinflammatory cytokine Kidney Tubules Proximal Mice Fibrosis Transforming Growth Factor beta Internal medicine medicine Renal fibrosis Animals PPAR alpha Kidney Nephritis biology Arginase Chemistry urogenital system Transforming growth factor beta medicine.disease Interleukin-10 MicroRNAs Endocrinology medicine.anatomical_structure Tubulointerstitial fibrosis biology.protein Call for Papers Aristolochic Acids Kidney Diseases B7-2 Antigen Laminin medicine.symptom Transforming growth factor Ureteral Obstruction |
| Zdroj: | American journal of physiology. Renal physiology. 305(5) |
| ISSN: | 1522-1466 |
| Popis: | We examined the effects of increased expression of proximal tubule peroxisome proliferator-activated receptor (PPAR)α in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction (UUO), PPARα expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARα transgenic (Tg) mice. When compared with wild-type mice subjected to UUO, PPARα Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-β1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, α-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARα Tg mice. Overexpression of PPARα in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid-mediated increased production of TGF-β, demonstrating PPARα signaling reduces epithelial TGF-β production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARα Tg mice after UUO. Increased expression of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in wild-type mice was also significantly reduced in kidney tissue of PPARα Tg mice. In contrast, the expression of anti-inflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARα Tg mice when compared with wild-type mice subjected to UUO. Our studies demonstrate several mechanisms by which preserved expression of proximal tubule PPARα reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy. |
| Databáze: | OpenAIRE |
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