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

Nath, Karl A.; Singh, Raman Deep; Croatt, Anthony J.; Ackerman, Allan W.; Grande, Joseph P.; Khazaie, Khasayarsha; Chen, Y Eugene; Zhang, Jifeng

doi:10.34067/kid.0002272022

Cited by 3 publications

(3 citation statements)

References 17 publications

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“…mRNA expression was assessed in cells and whole kidney tissues using a 2-step quantitative real-time RT-PCR method as employed in our previous studies (30,32). Briefly, RNA extraction was achieved using the TRIzol method (Invitrogen, Carlsbad, CA) with subsequent purification using a RNeasy Mini Kit (Qiagen, Valencia, CA).…”

Section: Assessment Of Gene Expressionmentioning

confidence: 99%

Prominent Mitochondrial Injury as an Early Event in Heme Protein-Induced Acute Kidney Injury

et al. 2022

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Background. Mitochondrial injury occurs in and underlies AKI caused by ischemia-reperfusion and other forms of renal injury. However, to-date, a comprehensive analysis of this issue has not been undertaken in heme protein-induced AKI (HP-AKI). We examined key aspects of mitochondrial function, expression of proteins relevant to mitochondrial quality control, and mitochondrial ultrastructure in heme protein-induced AKI, along with responses to heme in renal proximal tubule epithelial cells. Methods. The long-established murine glycerol model of HP-AKI was examined at 8 and 24 hours after HP-AKI. Indices of mitochondrial function (ATP and NAD+), expression of proteins relevant to mitochondrial dynamics, mitochondrial ultrastructure, and relevant gene/protein expression in heme-exposed renal proximal tubule epithelial cells in vitro were examined. Results. ATP and NAD+ content and the NAD+/NADH ratio were all reduced in HP-AKI. Expression of relevant proteins indicate that mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) and fusion (MFN2) were impaired, as was expression of key proteins involved in the integrity of outer and inner mitochondrial membranes (VDAC, Tom20, Tim23). Conversely, marked upregulation of proteins involved in mitochondrial fission (DRP1) occurred. Ultrastructural studies, including novel 3D imaging, indicate profound changes in mitochondrial structure, including mitochondrial fragmentation, mitochondrial swelling, and misshapen mitochondrial cristae; mitophagy was also observed. Exposure of renal proximal tubule epithelial cells to heme in vitro recapitulated suppression of PGC-1α (mitochondrial biogenesis) and upregulation of p-DRP1 (mitochondrial fission). Conclusion. Modern concepts pertaining to AKI apply to HP-AKI. This study validates the investigation of novel, clinically relevant therapies such as NAD+-boosting agents and mitoprotective agents in HP-AKI.

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Section: Assessment Of Gene Expressionmentioning

confidence: 99%

Prominent Mitochondrial Injury as an Early Event in Heme Protein-Induced Acute Kidney Injury

et al. 2022

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“…KLF4 and KLF11 have been shown to play important roles in endothelial cells in AKI. Loss of KLF4 in ischemia-reperfusion injury (IRI) results in increased expression of inflammatory and adhesion molecules, while translocation of KLF11 to the nucleus in IRI appears to be important in limiting endothelial activation [4, 5]. KLF2 also plays a role in the process of compensatory hypertrophy following uninephrectomy [6].…”

Section: Introductionmentioning

confidence: 99%

Roles of Krüppel-Like Transcription Factors KLF6 and KLF15 in Proximal Tubular Metabolism

Piret¹

2023

Nephron

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“…In this issue of Kidney360 , Nath et al (4) identify KLF11 as a novel protective factor with potential for therapeutic targeting in ischemic AKI. To investigate the role of KLF11 in kidney function during AKI, male KLF11 knockout and wild-type control mice were subjected to 22 minutes of bilateral ischemia-reperfusion injury (BIRI).…”

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Endothelial KLF11 as a Nephroprotectant in AKI

Ghajar-Rahimi

Agarwal

2022

Kidney360

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AKI is a common clinical problem with significant morbidity, mortality, and associated healthcare burden. AKI is caused by a wide range of etiologies, has no current treatment, and increases the risk of developing CKD. Despite the high mortality rate and incidence, no effective therapies to treat AKI have been successfully developed. The current mainstays of clinical management-supportive care and dialysisinadequately address the complexities of AKI and the AKI to CKD transition. The kidney contains numerous cell types and microenvironments, all of which respond differently to injury. Proximal tubule epithelial cells are often a main site of damage, particularly in ischemia-induced AKI. Other kidney compartments, including endothelial cells of the vasculature, immune cells, podocytes, and interstitial cells, are also involved in the pathogenesis of AKI. Novel therapies that consider all compartments of the kidney and the homeostasis that exists among them are therefore of great interest. Endogenous agents and signaling pathways in the kidney hold great potential to inform targeted therapeutic approaches and many, including Kr€ uppel-like factors (KLFs), have been the subject of preclinical studies. These, like most endogenous agents, have broad and pleiotropic influences on kidney function at baseline and injury. Understanding their molecular regulation in a cell-and injury statespecific manner will improve the development of novel, targeted therapeutics for AKI.KLFs have emerged in recent decades as critical factors in maintaining kidney homeostasis and influencing injury response. KLFs are a family of zinc-finger transcription factors involved in fundamental processes, including cellular cycling and differentiation, metabolism, and cell morphology. Of the 18 KLFs identified to date, several are found in the kidney. As reviewed by Mallipatu et al. (1), KLFs display cellspecific expression patterns throughout the kidney and serve diverse functions in maintaining homeostasis. For example, KLF6 and KLF15 influence TGF-b signaling and kidney fibrosis. Based on experiments in KLF11 knockout mice, KLF11 mitigates the severity of fibrosis in the unilateral ureteral obstruction model of CKD by inhibiting SMAD3-dependent TGF-b signal transduction (2). KLF2, KLF4, and KLF11 are expressed in kidney endothelial cells at baseline.

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

Abstract: This is an Early Access article. Please select the PDF button, above, to view it.

Cited by 3 publications

References 17 publications

Prominent Mitochondrial Injury as an Early Event in Heme Protein-Induced Acute Kidney Injury

Prominent Mitochondrial Injury as an Early Event in Heme Protein-Induced Acute Kidney Injury

Roles of Krüppel-Like Transcription Factors KLF6 and KLF15 in Proximal Tubular Metabolism

Endothelial KLF11 as a Nephroprotectant in AKI

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