The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis

Abstract

Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to progression of kidney fibrosis. Although canonical Wnt signaling can trigger activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Kruppel-Like Factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression is reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15fl/fl mice and accompanied by activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway.

Effect of sitagliptin on tubulointerstitial Wnt/β‐catenin signalling in diabetic nephropathy

“…Conversely, the overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. 32 The present findings demonstrate that high glucose treatment can induce Wnt4 activation in renal tubular epithelial cells, thereby activating the Wnt/β-catenin pathway to induce increased expression of α-SMA and decreased expression of E-cadherin. The exogenous administration of the Wnt blocker recombinant human dickkopf-related Protein-1(DKK-1) can attenuate the expression of collagen-1 and FN by inhibiting the activation of β-catenin signalling in a unilateral ureteral obstruction mouse model.…”

“…Recent studies have demonstrated that the loss of a Kruppel‐Like Factor 15 (KLF15) in cultured mouse embryonic fibroblasts, a kidney‐enriched zinc‐finger transcription factor, activated canonical Wnt/β‐catenin signalling, increased profibrotic transcription, and enhanced proliferation following treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho‐β‐catenin (Ser552) expression in Wnt1‐treated cells …”

Podocyte-Specific Induction of Krüppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease

“…Input (2%) of whole-cell lysates was immunoblotted with KLF15, WT1, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to detect protein expression as previously reported. 14…”

“…9,12 As such, we hypothesized that the induction of human KLF15 specifically in the podocyte might prevent podocyte injury in proteinuric murine models. Because KLF15 is expressed in several cell types in the kidney, 9,14 we initially generated mice with podocyte-specific expression of human KLF15 (KLF15) using the "tet-on" system on the FVB/N background, where the binding of chimeric tetracycline transactivator protein (rtTA) to tet-operator and gene activation only occurs in the presence of DOX (Supplemental Figure 1A). We bred the TRE-KLF15 mice with the Podocin-rtTA (PODTA) mice to generate mice with podocyte-specific expression of KLF15 in the setting of DOX administration on the FVB/N background strain.…”

Transactivation domain of Krüppel‐like factor 15 negatively regulates angiotensin II–induced adventitial inflammation and fibrosis

“…Previous studies have demonstrated that KLF15 regulates fibrotic factors contributing to kidney fibrosis in different kidney injury models (13, 28). It is reported that excessive collagen accumulation is mainly restricted to vascular adventitia (6, 17).…”