Loss of proximal tubular Kruppel-like factor 15 (KLF15) exacerbates kidney injury through loss of fatty acid oxidation

KLF15 has a critical role in other kidney cell types, but its role in mediating proximal tubular (PT) fatty acid oxidation (FAO) in AKI has not been determined. PT-specific KLF15 knockdown (Klf15PTKO) and control Klf15fl/fl mice were treated with multiple low doses of the PT-specific DNA-damaging agent aristolochic acid I (AAI) and RNA-sequencing of kidney cortex undertaken. Klf15PTKO exhibited worse kidney injury than Klf15fl/fl mice after AAI treatment. Immune system and integrin signaling pathways were significantly upregulated in Klf15PTKO versus Klf15fl/fl mice. Metabolic pathways, specifically FAO, were significantly downregulated in Klf15PTKO versus Klf15fl/fl mice, including PPARalpha signaling. Kidney cortex mRNA profiles were generated in Klf15fl/fl and Klf15PTKO mice treated with DMSO or AAI for 2 weeks or AAI for 2 weeks followed by 2 weeks remodeling time using RNA-sequencing.