Podocyte-specific induction of Krüppel-like factor 15 restores differentiation markers and attenuates kidney injury in proteinuric kidney disease

Podocyte injury is the hallmark of proteinuric kidney diseases, such as Focal Segmental Glomerulosclerosis and Minimal Change Disease. Therapeutic strategies in the management of proteinuric diseases are limited. Although agents such as glucocorticoids, cyclosporine, and rituximab have direct effects on the podocyte by stabilizing its actin cytoskeleton, these drugs are riddled with systemic toxicity and off-target effects that hinder their chronic use. We previously demonstrated that the loss of the kidney-enriched zinc finger transcription factor, Krüppel-like factor 15 (KLF15), increases susceptibility to proteinuric kidney disease as well as attenuates the salutary effects of retinoic acid and glucocorticoids in the podocyte. Here, we show that podocyte-specific induction of KLF15, using the tetracycline-inducible system, attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis and inflammation, while improving renal function and overall survival in HIV-1 transgenic mice. Enrichment analysis of mRNA sequencing of isolated glomerular extracts from this model shows that podocyte-specific induction of KLF15 activates pathways involved in stabilization of actin cytoskeleton, focal adhesion, and podocyte differentiation. Transcription factor enrichment analysis, with further experimental validation, suggests that KLF15 activity is in part mediated by Wilms Tumor 1 (WT1), a transcription factor known to be critical for podocyte differentiation. Further, we confirmed the benefits of podocyte-specific induction of KLF15 in the adriamycin-induced proteinuric murine model. Collectively, these observations suggest that induction of KLF15 might be a potential therapeutic target in the treatment of proteinuric kidney disease. Overall design: Transcriptome analysis of Tg26 and Tg26 KLF15OE