Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation

• Published in: Kidney international Vol. 100; no. 6; pp. 1250 - 1267
• Main Authors: Piret, Sian E., Attallah, Ahmed A., Gu, Xiangchen, Guo, Yiqing, Gujarati, Nehaben A., Henein, Justina, Zollman, Amy, Hato, Takashi, Ma’ayan, Avi, Revelo, Monica P., Dickman, Kathleen G., Chen, Chung-Hsin, Shun, Chia-Tung, Rosenquist, Thomas A., He, John C., Mallipattu, Sandeep K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2021
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - genetics; AKI; Animals; fatty acid oxidation; Fatty Acids - metabolism; Kidney; kidney fibrosis; Kidney Tubules, Proximal; KLF15; Kruppel-Like Transcription Factors - genetics; Mice; Mice, Knockout; PPARα; proximal tubule; fatty acid oxidation; PPARα; proximal tubule; KLF15; kidney fibrosis; AKI
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1016/j.kint.2021.08.031

Loss of fatty acid β-oxidation (FAO) in the proximal tubule is a critical mediator of acute kidney injury and eventual fibrosis. However, transcriptional mediators of FAO in proximal tubule injury remain understudied. Krüppel-like factor 15 (KLF15), a highly enriched zinc-finger transcription factor in the proximal tubule, was significantly reduced in proximal tubule cells after aristolochic acid I (AAI) treatment, a proximal tubule-specific injury model. Proximal tubule specific knockout of Klf15 exacerbated proximal tubule injury and kidney function decline compared to control mice during the active phase of AAI treatment, and after ischemia-reperfusion injury. Furthermore, along with worsening proximal tubule injury and kidney function decline, knockout mice exhibited increased kidney fibrosis as compared to control mice during the remodeling phase after AAI treatment. RNA-sequencing of kidney cortex demonstrated increased transcripts involved in immune system and integrin signaling pathways and decreased transcripts encompassing metabolic pathways, specifically FAO, and PPARα signaling, in knockout versus control mice after AAI treatment. In silico and experimental chromatin immunoprecipitation studies collectively demonstrated that KLF15 occupied the promoter region of key FAO genes, CPT1A and ACAA2, in close proximity to transcription factor PPARα binding sites. While the loss of Klf15 reduced the expression of Cpt1a and Acaa2 and led to compromised FAO, induction of KLF15 partially rescued loss of FAO in AAI-treated cells. Klf15, Ppara, Cpt1a, and Acaa2 expression was also decreased in other mouse kidney injury models. Tubulointerstitial KLF15 independently correlated with eGFR, PPARA and CPT1A appearance in expression arrays from human kidney biopsies. Thus, proximal tubule-specific loss of Klf15 exacerbates acute kidney injury and fibrosis, likely due to loss of interaction with PPARα leading to loss of FAO gene transcription. [Display omitted]