Endothelial KLF11 as a Nephroprotectant in AKI

Abstract

AKI is a common clinical problem with significant morbidity, mortality, and associated healthcare burden. AKI is caused by a wide range of etiologies, has no current treatment, and increases the risk of developing CKD. Despite the high mortality rate and incidence, no effective therapies to treat AKI have been successfully developed. The current mainstays of clinical management-supportive care and dialysisinadequately address the complexities of AKI and the AKI to CKD transition. The kidney contains numerous cell types and microenvironments, all of which respond differently to injury. Proximal tubule epithelial cells are often a main site of damage, particularly in ischemia-induced AKI. Other kidney compartments, including endothelial cells of the vasculature, immune cells, podocytes, and interstitial cells, are also involved in the pathogenesis of AKI. Novel therapies that consider all compartments of the kidney and the homeostasis that exists among them are therefore of great interest. Endogenous agents and signaling pathways in the kidney hold great potential to inform targeted therapeutic approaches and many, including Kr€ uppel-like factors (KLFs), have been the subject of preclinical studies. These, like most endogenous agents, have broad and pleiotropic influences on kidney function at baseline and injury. Understanding their molecular regulation in a cell-and injury statespecific manner will improve the development of novel, targeted therapeutics for AKI.KLFs have emerged in recent decades as critical factors in maintaining kidney homeostasis and influencing injury response. KLFs are a family of zinc-finger transcription factors involved in fundamental processes, including cellular cycling and differentiation, metabolism, and cell morphology. Of the 18 KLFs identified to date, several are found in the kidney. As reviewed by Mallipatu et al. (1), KLFs display cellspecific expression patterns throughout the kidney and serve diverse functions in maintaining homeostasis. For example, KLF6 and KLF15 influence TGF-b signaling and kidney fibrosis. Based on experiments in KLF11 knockout mice, KLF11 mitigates the severity of fibrosis in the unilateral ureteral obstruction model of CKD by inhibiting SMAD3-dependent TGF-b signal transduction (2). KLF2, KLF4, and KLF11 are expressed in kidney endothelial cells at baseline.