KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

Abstract

Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-β/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.

An integrated co-expression network analysis reveals novel genetic biomarkers for immune cell infiltration in chronic kidney disease

“…Among the PBMC common hub genes, several genes have been reported to be associated with kidney disease or hematologic disorder. KLF11 is a Krüppel-type zinc finger protein whose deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction (27) and highly induced by TGF-b (28). It has been reported that KLF11 inhibits the activity of SMAD7 and enhances TGF-b pathway activation (29), through which KLF11 may influence the lymphocyte function.…”

SKP2‐mediated ubiquitination and degradation of KLF11 promotes osteoarthritis via modulation of JMJD3/NOTCH1 pathway

“…As a zinc-finger transcription factor, KLF11 is involved in the regulation of various pathophysiological processes, such as growth, development, fibrosis, and inflammatory response. 5 For instance, KLF11 was reported to protect against cardiac hypertrophy and fibrosis in mice. 6 A recent study reported the differential expression of KLF11 in the OA cartilage specimens.…”

KLF11 Is a Novel Endogenous Protectant against Renal Ischemia-Reperfusion Injury

“…Interestingly, De Lorenzo et al . have just demonstrated that KLF11 reduces chronic kidney injury (unilateral ureteral obstruction) by inhibiting the TGF- β 1/Smad3 pathway (10).…”

“…We thus hypothesize that KLF11 protects against IRI because it suppresses renal production of ET-1 and inflammation. Interestingly, De Lorenzo et al have just demonstrated that KLF11 reduces chronic kidney injury (unilateral ureteral obstruction) by inhibiting the TGF-b1/Smad3 pathway (10).…”