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Loss of Krüppel-Like Factor 6 Cripples Podocyte Mitochondrial Function

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Loss of Krüppel-Like Factor 6 Cripples Podocyte Mitochondrial Function Loss of Krüppel-like factor 6 cripples podocyte mitochondrial function Jeffrey B. Kopp J Clin Invest. 2015;125(3):968-971. https://doi.org/10.1172/JCI80280. Commentary Krüppel-like factors (KLFs) are zinc finger transcription factors that share homology in three C-terminal zinc finger domains. KLF family members are expressed in most if not all tissues and have diverse roles in organismal development and cell differentiation, function, and death. The glomerular podocyte is particularly sensitive to mitochondrial dysfunction, as seen in various genetic disorders manifesting as progressive glomerulosclerosis. In this issue of the JCI, Mallipattu and coworkers show that KLF6 expression is reduced in mouse and human glomerular disease. Podocyte-specific deletion of Klf6 expression in mice leads to mitochondrial dysfunction and apoptosis, followed by glomerulosclerosis. This is the first demonstration that defective transcriptional regulation of nuclear-encoded mitochondrial genes can result in experimental glomerular disease. Find the latest version: https://jci.me/80280/pdf COMMENTARY The Journal of Clinical Investigation Loss of Krüppel-like factor 6 cripples podocyte mitochondrial function Jeffrey B. Kopp Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA. activators, and group 3 KLFs bind and Krüppel-like factors (KLFs) are zinc finger transcription factors that share potentiate the activity of the co-repres- sor SIN3A; KLF16 and -17 do not cluster homology in three C-terminal zinc finger domains. KLF family members with other group members (ref. 6 and Fig- are expressed in most if not all tissues and have diverse roles in organismal ure 2). Expression of some KLFs is tissue development and cell differentiation, function, and death. The glomerular restricted, such as KLF1 in hematopoietic podocyte is particularly sensitive to mitochondrial dysfunction, as seen in cells, while others are widely expressed. various genetic disorders manifesting as progressive glomerulosclerosis. In This class of transcription factors has this issue of the JCI, Mallipattu and coworkers show that KLF6 expression highly diverse roles that include regulat- is reduced in mouse and human glomerular disease. Podocyte-specific ing cell growth, differentiation, and death; deletion of Klf6 expression in mice leads to mitochondrial dysfunction and endothelial and epithelial function; fat and apoptosis, followed by glomerulosclerosis. This is the first demonstration glucose metabolism; and mitochondrial that defective transcriptional regulation of nuclear-encoded mitochondrial function; among other effects (6). Shinya genes can result in experimental glomerular disease. Yamanaka and colleagues have shown that KLF4 is one of a set of four transcription factors (the others being OCT4, SOX2, and MYC) that can reprogram adult cells Krüppel and Krüppel-like (Figure 1). The highly conserved zinc to become induced pluripotent stem cells factors finger domains comprise three sets of (7), a discovery that resulted in Yamanaka The 1995 Nobel Prize in Physiology or Cys2/His2 amino acid residues located sharing the 2012 Nobel Prize in Physiology Medicine was award to Edward B. Lewis, at the C terminus, which are also similar or Medicine with John Gurdon. As tran- Christiane Nüsslein-Volhard, and Eric F. to three motifs in the transcription factor scriptional factors, KLFs are present in the Wieschaus for their work on embryonic SP1 (Figure 1). The zinc finger motifs of nucleus, but they are also present in the development of Drosophila melanogaster, members of the KLF and SP1 superfamily cytoplasm and have distinct roles there. particularly with regard to homeotic of transcriptional regulators bind GC-rich genes that regulate development in plants motifs in gene regulatory regions, and KLFs have diverse roles and animals. Perhaps best known among they act as generally weak activators in kidney physiology and the homeotic genes are those that encode and often as strong repressors of gene pathophysiology the homeobox (Hox and ParaHox) pro- expression. KLFs bound to DNA attract Glomerular endothelial cells that are teins, which regulate other gene families partners. For group 2 KLFs such as KLF4, exposed in vitro to laminar shear stress (1). In 1950, Gloor described a fly mutant which are transcriptional activators, these express higher levels of KLF2, leading Slater that caused severe body malformation, may include CBP/p300 (4). For example, et al. to suggest that this might contribute to which he named Krüppel, meaning “crip- KLF4 binds a TGF-β transcriptional con- the phenotype-stabilizing effects of shear ple” (2). Nüsslein-Volhard and Wieschaus trol element located in the angiotensin stress on the vascular endothelium (8). showed that Krüppel mutations disrupt II type 1 receptor (ATR1). In response to Compared with WT mice, animals with a Drosophila body segmentation at very TGF-β signaling, SP1 dissociates from endothelial-specific deletion of Klf2 mani- early stages of embryogenesis, leading to KLF4 and PPARγ binds KLF4, resulting in fest a more severe streptozotocin-diabetic embryonic lethality (3). enhanced ATR1 transcription (5). nephropathy, including more proteinuria, Mammalian genomes contain many The human genome contains 17 more glomerular hypertrophy, and evidence genes that encode orthologs of Drosophila KLF-encoding genes and can be classified of more endothelial injury but interestingly Krüppel, termed Krüppel-like factors into three phylogenetic groups that cor- also more severe podocyte injury (9). In a (KLFs). KLFs manifest amino acid homol- relate with functional differences: group 1 study of glomerular transcripts expressed in ogy to Krüppel in the three DNA-binding KLFs are transcriptional repressors, group atypical hemolytic uremic syndrome, KLF4 zinc fingers located at the C terminus 2 KLFs are predominantly transcriptional expression was modestly elevated (10); on the other hand, KLF2 and KLF4 transcripts were reduced in glomerular transcripts from Related Article: p. 1347 renal transplant–associated thrombotic Conflict of interest: The author has declared that no conflict of interest exists. microangiopathy (11), suggesting a complex Reference information: J Clin Invest. 2015;125(3):968–971. doi:10.1172/JCI80280. picture for KLF-mediated gene expression. 968 jci.org Volume 125 Number 3 March 2015 The Journal of Clinical Investigation COMMENTARY genetic disorders that alter mitochon- dria can affect all tissues. With regard to kidney phenotypes, mitochondrial dis- orders may manifest as proximal tubu- lar dysfunction with loss of electrolytes, glucose, amino acids, and low-molec- ular-weight proteins; tubulointerstitial disease and cystic kidney disease; and podocytopathy with subnephrotic or Figure 1. The KLF family of transcription factors. (A) KLF family members all contain three highly nephrotic proteinuria. conserved zinc finger domains within their C terminus that bind to GC-rich regions in DNA. These three zinc finger domains insert into the major groove of the DNA helix. B( ) KLF transcription factors Further insight into the role of generally bind proximal to the transcriptional start site, acting as transcriptional promoters. In the case of KLF4 bound to the angiotensin II receptor type 1 gene, the binding of SP1 confers inhibition of KLF6 in podocyte biology transcription. In the presence of TGF-β, SP1 dissociates from KLF4 and PPARγ binds, which promotes In this issue, Mallipattu and coworkers transcriptional initiation. present three lines of evidence that sup- port a role for KLF6 in maintaining normal podocyte function and specifically link this In contrast to the predominantly endo- knockdown of KLF2 increased cell prolif- to the ability of KLF6 to support podocyte thelial expression pattern of KLF2 and eration (17). In cultured human podocytes, mitochondrial function (22). KLF4, KLF5 is expressed in collecting duct retinoids were shown to increase KLF15 First, Mallipattu et al. surveyed renal epithelial cells and plays a role in inflam- expression, and KLF15 drove podocyte expression of 9 KLFs in HIV-infected mation and fibrosis. Mice haploinsufficient differentiation in vitro, binding to the pro- human podocytes and in HIV-transgenic for Klf5 exhibit less renal injury following moter regions of nephrin and podocin as mice (23) that manifest with HIV-associ- unilateral ureteral ligation and an apparent shown by ChIP assay (18). Further, Klf15- ated nephropathy (collapsing glomerulop- shift from M1 macrophages to M2 macro- knockout mice manifest more podocyte athy). It is currently thought that podocyte phages, which would be compatible with a injury in response to the podocyte toxins injury and loss lead to podocyte replace- less fibrotic outcome (12). LPS and doxorubicin, suggesting a pheno- ment from several sources, particularly During metanephric development, type-stabilizing role for KLF15. parietal epithelial stem cells and cells of Klf6 is expressed in the Wolffian duct the renin lineage. A survey of the mRNA and its derivatives and in the ureteric KLFs and mitochondria expression patterns of KLF family mem- bud and its branches, including the KLFs have previously been associated with bers revealed that only KLF6 expression distal tubule, with limited glomerular regulation of mitochondria number and was altered, with it being reduced in both staining seen in what was interpreted function. Mitochondria are heterogeneous HIV-infected podocytes
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