The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis
Autor: | Vincent W. Yang, Yiqing Guo, Xiang Gao, Monica P. Revelo, Mukesh K. Jain, Timothy Miller, Sandeep K. Mallipattu, Agnieszka B. Bialkowska, John Cijiang He, Changlin Mei, Xiangchen Gu, Jesse Pace |
---|---|
Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Pathology medicine.medical_specialty Stromal cell Kruppel-Like Transcription Factors 030232 urology & nephrology Wnt1 Protein Biology Kidney Article Mice 03 medical and health sciences 0302 clinical medicine Fibrosis medicine Renal fibrosis Animals RNA Messenger Phosphorylation Myofibroblasts Wnt Signaling Pathway Cells Cultured beta Catenin Cell Proliferation Angiotensin II Wnt signaling pathway Acute kidney injury Forkhead Transcription Factors medicine.disease DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Nephrology Gene Knockdown Techniques Disease Progression Cancer research Kidney Diseases Stromal Cells Myofibroblast Transcription Factors |
Zdroj: | Kidney International. 92:1178-1193 |
ISSN: | 0085-2538 |
Popis: | Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to the progression of kidney fibrosis. Although canonical Wnt signaling can trigger the activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Kruppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression are reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis. Knockdown of Klf15 in Foxd1 -expressing cells ( Foxd1-Cre Klf15fl/fl ) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype ( Foxd1-Cre Klf15+/+ ) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15 fl/fl mice and accompanied by the activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway. |
Databáze: | OpenAIRE |
Externí odkaz: |