Hypoxia-inducible factor-1α activation can attenuate renal podocyte injury and alleviate proteinuria in rats in a simulated high-altitude environment

Cheng, Yue; Li, Y.; Zeng, Xiao-shan; Wang, Tao; Zhang, Fan; Zhang, Yaolei

doi:10.1016/j.bbrc.2022.02.091

Cited by 4 publications

(7 citation statements)

References 18 publications

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“…After rats spent 14 days in a simulated high-altitude environment (5,000 m), electron microscopy showed podocyte injury in their kidneys. The protein levels of CD2-associated proteins and nephrin in the glomeruli were lower than those in the control group, possibly related to proteinuria after short-term high-altitude exposure ( Zeng et al, 2022 ). NO is also a component of the hypoxia response.…”

Section: Physiological Changesmentioning

confidence: 92%

Effects of high altitude on renal physiology and kidney diseases

Wang

Gao²,

Zhao³

2022

Front. Physiol.

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The hypobaric and hypoxic conditions of high-altitude areas exert adverse effects on the respiratory, circulatory and nervous systems. The kidneys have an abundant blood supply (20%–25% of cardiac output) and high blood flow; thus, they are susceptible to the effects of hypoxia. However, the effects of acute and chronic exposure to high altitudes on renal physiology and pathology are not fully understood. Moreover, few studies have investigated the impact of high-altitude exposure on patients with chronic kidney disease or acute kidney injury. In this review, we summarized changes in renal physiology and renal pathology due to high-altitude exposure as well as the impact of high-altitude exposure on existing kidney diseases, with the aim of informing the prevention and treatment of kidney diseases at high altitudes.

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Section: Physiological Changesmentioning

confidence: 92%

Effects of high altitude on renal physiology and kidney diseases

Wang

Gao²,

Zhao³

2022

Front. Physiol.

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“…[64][65][66][67] When transient, the coordinated actions of these metabolic and regulatory shifts are highly beneficial, and they protect against AKI produced by hypoxia, contrast agents, nephrotoxic drugs, or systemic inflammation. [68][69][70][71][72] However, if the stress or injury is sustained, persistence of the fetal phenotype over prolonged periods is deleterious to renal homeostasis and survival, especially because the fetal program is activated in a proximal renal tubule that is functioning in a normoxic high-workload environment, instead of the primordial hypoxic low-workload setting of embryonic development. [64][65][66][67] CKD is characterized by sustained upregulation of mTOR and HIF-1a, both of which act to enhance oxidative stress (particularly in the proximal tubule) 73 and to promote renal inflammation, apoptosis, and fibrosis, [74][75][76][77] especially when nutrient deprivation signaling through SIRT1 and AMPK is simultaneously suppressed.…”

Section: Renal Injury and Stress Causes Recapitulation Of The Fetal P...mentioning

confidence: 99%

“…64–67 When transient, the coordinated actions of these metabolic and regulatory shifts are highly beneficial, and they protect against AKI produced by hypoxia, contrast agents, nephrotoxic drugs, or systemic inflammation. 68–72…”

Section: Nutrient Surplus Signaling and The Fetal And Injured Adult K...mentioning

confidence: 99%

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

Packer

2023

JASN

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Fetal kidneys have increased uptake of glucose, ATP production by glycolysis, and upregulation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α). These interacting processes promote nephrogenesis in a hypoxic low-tubular-workload environment. In contrast, the healthy adult kidney upregulates sirtuin-1 and adenosine monophosphate-activated protein kinase, which enhances ATP production through fatty-acid oxidation, in a normoxic high-tubular-workload environment. During stress or injury, the kidney reverts to a fetal signaling program that is adaptive in the short-term, but deleterious if sustained with heightened oxygen tension and tubular workloads. Prolonged increase in glucose uptake in glomerular and proximal tubular cells leads to enhanced flux through the hexosamine biosynthesis pathway. The endproduct — uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) — drives the rapid and reversible O-GlcNAcylation of thousands of intracellular proteins, most not membrane-bound or secreted. O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas hundreds of kinases and phosphatases regulate phosphorylation, only O-GlcNAc transferase and O-GlcNAcase, which add or remove O-GlcNAc from target proteins, regulate O-GlcNAcylation. Fetal reprogramming (upregulating mTOR and HIF-1α) and increased O-GlcNAcylation occur in diabetic and nondiabetic CKD, experimentally and clinically. Augmentation of O-GlcNAcylation in the adult kidney enhances oxidative stress, cell cycle entry, and apoptosis, activates proinflammatory and profibrotic pathways, and inhibits megalin-mediated albumin endocytosis in glomerular mesangial and proximal tubular cells, which muting of O-GlcNAcylation can aggravate and attenuate, respectively. Additionally, some nephroprotective drugs are associated with diminished O-GlcNAcylation in the kidney. Evidence supports further investigation of UDP-GlcNAc as a critical nutrient surplus sensor in the development of diabetic and nondiabetic CKD.

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“…Our previous studies have shown that proteinuria occurs in rats in a simulated high‐altitude environment of 5000 m. Along with proteinuria, podocyte lesions such as swelling and foot process fusion were detected, indicating that the hypobaric and hypoxic environment at high altitudes can cause some degree of podocyte injury in rats, which may contribute to the development of proteinuria in high‐altitude regions. However, prolonging the simulated high‐altitude feeding time resulted in an initial increase and then a decreasing trend in urinary protein levels, indicating an adaptive regulatory mechanism in response to acute hypobaric hypoxia‐induced proteinuria (Zeng et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1α attenuates renal podocyte injury in male rats in a simulated high‐altitude environment by upregulating Krüppel‐like factor 4 expression

Xiaoshan,

Huan,

Zhilin

et al. 2024

Experimental Physiology

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Previous studies have shown that podocyte injury is involved in the development of proteinuria in rats under hypobaric hypoxia conditions. Prolyl hydroxylase inhibitors (PHIs) may reduce proteinuria. This study aimed to further investigate whether the protective effects of hypoxia‐inducible factor 1α (HIF1α) on podocyte injury induced by hypobaric hypoxia are related to Krüppel‐like factor 4 (KLF4). Rats were housed in a low‐pressure oxygen chamber to simulate a high‐altitude environment (5000 m), and a PHI was intraperitoneally injected. Urinary protein electrophoresis was performed and the morphology of the podocytes was observed by electron microscopy. Rat podocytes were cultured under 1% O2, and siRNA was used to interfere with KLF4 expression. The protein expression levels of HIF1α, KLF4, CD2‐associated protein (CD2AP) and nephrin were determined by western blotting. Compared with those in the experimental group, the rats in the intervention group on day 14 had lower urinary protein levels, increased protein expression levels of CD2AP and nephrin, and reduced podocyte injury. The results of in vitro experiments showed that the protein expression levels of KLF4, CD2AP and nephrin were greater in the PHI intervention group and lower in the HIF1α inhibitors group than in the low‐oxygen group. The protein expression of CD2AP and nephrin in the siKLF4‐transfected podocytes treated with PHI and HIF1α inhibitors did not differ significantly from that in the low‐oxygen group. HIF1α may be involved in reducing progressive high‐altitude proteinuria by regulating KLF4 expression and contributing to the repair of podocyte injury induced by hypobaric hypoxia.

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Hypoxia-inducible factor-1α activation can attenuate renal podocyte injury and alleviate proteinuria in rats in a simulated high-altitude environment

Cited by 4 publications

References 18 publications

Effects of high altitude on renal physiology and kidney diseases

Effects of high altitude on renal physiology and kidney diseases

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

Hypoxia‐inducible factor‐1α attenuates renal podocyte injury in male rats in a simulated high‐altitude environment by upregulating Krüppel‐like factor 4 expression

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