The critical role of Krüppel-like factors in kidney disease

Mallipattu, Sandeep K.; Estrada, Chelsea; He, John Cijiang

doi:10.1152/ajprenal.00550.2016

Cited by 39 publications

(40 citation statements)

References 57 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genes associated with promoting proliferation and fibrosis such as Grem1, Grem2 [24,25], and Ctgf were significantly upregulated in the kidney cortices of diabetic mice; however, the expression of these genes was downregulated following treatment with rosiglitazone. Furthermore, increasing attention has been given to the potential role that Kruppel-like factors (KLFs) have in kidney disease, especially in diabetic nephropathy [26,27]. Specifically, the profibrotic KLF10 and KLF11 and the proinflammatory KLF13 [28,29] have been shown to be significantly upregulated in DN, yet, in our study, rosiglitazone treatment served to reverse this overexpression, which may underline the new renoprotective mechanism of rosiglitazone, and further investigations are needed to confirm their role in DN.…”

Section: Discussionmentioning

confidence: 64%

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Zhang

Zhou

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Diabetic nephropathy (DN) is characterized by metabolic disorder and inflammation. However, the regulatory effects that long noncoding RNAs (lncRNAs) have on the pathogenesis of DN and on the efficacy of rosiglitazone treatment have yet to be clearly defined. Herein, we performed unbiased RNA sequencing to characterize the transcriptomic profiles in db/db diabetic mouse model with or without rosiglitazone treatment that served to improve the phenotypes of DN. Moreover, RNA-seq profiling revealed that the development of DN caused an upregulation in the expression of 1176 mRNAs and a downregulation in the expression of 1010 mRNAs compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with rosiglitazone. Further, 88 upregulated and 68 downregulated lncRNAs were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with rosiglitazone. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARc, are related to inflammatory and metabolic processes. From bioinformatics analysis, lncRNA-AI838599 emerged as a novel molecular mechanism for rosiglitazone treatment in DN through TNFα-NFκb pathway. ese findings may indicate a new molecular regulatory approach for the development of DN therapeutic agents.

show abstract

Section: Discussionmentioning

confidence: 64%

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Zhang

Zhou

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…In practice, however, extrapolating methylation changes at a given locus to a global picture of the epigenome in the uremic environment is challenging and complex. observed for Krüppel-like transcription factor 2, which has a role in regulating blood flow through the glomerular kidney bed and regulation of most of the nuclear factor kappa B (NF-ΚB)-mediated activities, including inflammatory and fibrotic processes (27). This provides a rational basis for linking changes in epigenetic status with renal function in CKD.…”

Section: The Principles and The Evidence For Methylation Dynamics In Ckdmentioning

confidence: 95%

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape

Mafra

Esgalhado²,

Borges

et al. 2019

The Journal of Nutrition

View full text Add to dashboard Cite

Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.

show abstract

“…Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that exert diverse effects on key biologic processes, including tumorigenesis, immune cell activation, and pluripotency (10,11). Although several members in the family have been implicated in cell differentiation (11)(12)(13), KLF4 was first identified as a negative regulator of proliferation by inducing cell-cycle arrest and restoring prodifferentiation markers in intestinal epithelial cells (10,14).…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation

Estrada¹,

Paladugu²,

Guo³

et al. 2018

JCI Insight

Self Cite

View full text Add to dashboard Cite

Pathologic glomerular epithelial cell (GEC) hyperplasia is characteristic of both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Although initial podocyte injury resulting in activation of STAT3 signals GEC proliferation in both diseases, mechanisms regulating this are unknown. Here, we show that the loss of Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, enhances GEC proliferation in both RPGN and FSGS due to dysregulated STAT3 signaling. We observed that podocyte-specific knockdown of Klf4 (C57BL/6J) increased STAT3 signaling and exacerbated crescent formation after nephrotoxic serum treatment. Interestingly, podocyte-specific knockdown of Klf4 in the FVB/N background alone was sufficient to activate STAT3 signaling, resulting in FSGS with extracapillary proliferation, as well as renal failure and reduced survival. In cultured podocytes, loss of KLF4 resulted in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. This triggered IL-6 release into the supernatant, which activated STAT3 signaling in parietal epithelial cells. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. Finally, human kidney biopsy specimens with RPGN exhibited reduced KLF4 expression with a concomitant increase in phospho-STAT3 expression as compared with controls. Collectively, these results suggest the essential role of KLF4/STAT3 signaling in podocyte injury and its regulation of aberrant GEC proliferation.

show abstract

The critical role of Krüppel-like factors in kidney disease

Cited by 39 publications

References 57 publications

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape

Krüppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation

Contact Info

Product

Resources

About