SAT-177 KLF11 DEFICIENCY EXACERBATES RENAL INJURY IN EXPERIMENTAL UNILATERAL URETERIC OBSTRUCTION

Abstract

Kruppel-like factors (KLFs) are a family of zinc-finger transcription factors that play a critical role in regulation of growth and development, proliferation, and regeneration. Members of this family have been linked to podocyte dysfunction and renal fibrosis. In other systems, KLF11 has been shown to regulate TGF-beta signaling and fibrosis. Although KLF deficiency has been linked to endometriosis-related fibrosis, the role of KLF11 in mediating renal injury has not been previously established. We sought to test the hypothesis that KLF11 deficiency exacerbates renal damage in the murine unilateral ureteral obstruction (UUO) of renal fibrosis. We generated KLF11 knockout (KO), Smad 3 wild type (WT) mice, KLF11 WT Smad 3 KO, KLF11 KO Smad 3 KO, and KLF11/Smad3 WT mice and performed unilateral ureteral obstruction. Kidneys were harvested after 9 days (n=4 animals per group). Semiquantitative histopathologic analysis of renal atrophy, fibrosis, and inflammation was performed in a blinded fashion. Gene expression analysis was performed on renal cortex using Pathway Detect RNA Arrays. Renal atrophy (Figure 1) and inflammation (data not shown) were increased in KLF11 KO Smad3 WT mice compared to WT/WT mice subjected to UUO. As expected, Smad3 deficiency was associated with significantly less renal injury (Figure 1). Compared to WT/WT mice, KLF11 KO Smad3 WT mice showed marked upregulation of pro-inflammatory chemokines including CCL7 (250-fold compared to sham), Cxcl 11 (170-fold), Ccl12 (143-fold), Csf1 (117-fold), Ccl5 (96-fold), and Ccl2 (76-fold), inductions that were 2-5 fold higher than those observed in WT/WT mice. KLF11 deficiency was associated with modest upregulation of pro-fibrotic genes including Col1a2, Col1a1, and TGF-beta 1-3. Smad3 deficiency was associated with significant reduction of both pro-inflammatory and pro-fibrotic genes, both in the presence and absence of Klf11 deficiency. KLF11 deficiency exacerbates renal injury in the UUO model of renal fibrosis through upregulation of pro-inflammatory chemokine genes. To our knowledge, this is the first report linking KLF11 signaling to renal injury. Future studies will focus on potential mechanisms whereby KLF11 mediated chemokine signaling intersects with TGF-beta/Smad signaling to produce renal injury.