Hypoxia inducible factor in nephrotoxicity

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This entry is adapted from the peer-reviewed paper 10.3390/cancers13020180

Cisplatin is a highly effective, broad-spectrum chemotherapeutic drug, yet its clinical use and efficacy are limited by its side effects. Particularly, cancer patients receiving cisplatin chemotherapy have high incidence of kidney problems. Hypoxia-inducible factor (HIF) is the “master” transcription factor that is induced under hypoxia to trans-activate various genes for adaptation to the low oxygen condition. Numerous studies have reported that HIF activation protects against AKI and promotes kidney recovery in experimental models of cisplatin-induced acute kidney injury (AKI). In contrast, little is known about the effects of HIF on chronic kidney problems following cisplatin chemotherapy. Prolyl hydroxylase (PHD) inhibitors are potent HIF inducers that recently entered clinical use. By inducing HIF, PHD inhibitors may protect kidneys during cisplatin chemotherapy. However, HIF activation by PHD inhibitors may reduce the anti-cancer effect of cisplatin in tumors.

cisplatin HIF hypoxia acute kidney injury chronic kidney disease

1. Introduction

Cisplatin is an effective and broad-spectrum chemotherapeutic agent for various kind of tumors. Though being used worldwide, the therapeutic efficacy of cisplatin is limited, to some extent, by its side effects in normal tissues including ototoxicity, neurotoxicity, and nephrotoxicity^[1]. Among them, cisplatin-induced kidney injury or nephrotoxicity is life-threatening and has attracted great attention with numerous studies focusing on its underlying mechanisms and potential therapeutic strategies^[2]^[3]. Cisplatin can induce both acute kidney injury (AKI)^[3]^[4] and the chronic kidney diseases (CKD) following AKI^[5]^[6]^[7].

Hypoxia is a common factor involved in the development of renal pathology in both AKI and CKD [10]. Hypoxia-inducible factor(HIF) is generally considered as the core regulator for maintaining oxygen homeostasis due to its crucial role in cellular sensing and adaption to hypoxia^[8]^[9]^[10]. As a transcription factor, HIF binds to DNA in a sequence-specific manner to promote or repress the transcription of multiple genes. HIF is widely involved in various biological processes, such as oxygen sensing, angiogenesis, vasodilation, erythropoiesis, metabolism, inflammation, and cell-cycle regulation^[11]^[12]. Several studies have reported that HIF may participate in cisplatin-induced nephrotoxicity. However, most of these studies focus on cisplatin-induced AKI and find that HIF activation may protect against tubular cell injury and promote kidney recovery^[13]^[14]^[15]^[16]. The lack of information of HIF in AKI to CKD progression and chronic kidney problems following cisplatin exposure make it an urgent need to study the regulation of HIF in these conditions.

Hypoxia is a known condition in solid tumors due to abnormal cancer cellular proliferation, expansion of tumor size and disruption of angiogenesis. As such, HIF is activated in tumors for cellular adaptation, and studies have found that inhibition of HIF may be an anti-cancer strategy under some circumstances ^[17]. In cisplatin chemotherapy, the activation of HIF for kidney protection may therefore antagonize the anti-tumor effects. Thus, when considering HIF activation as a kidney-protective strategy in cisplatin chemotherapy, the effect on cisplatin's anti-tumor efficiency has to be taken into consideration.

2. HIF in Cisplatin-Induced AKI

Over the past few decades, several studies demonstrated the evidence for a reno-protective role of HIF in cisplatin-induced AKI. These studies are summarized in Table 1.

Table 1. Summary of studies about the role of HIF in cisplatin-induced AKI.

Number	Model	Strategies for HIF Regulation	Involved HIF Isoforms	Is HIF Activated or Inhibited	Effects	Underlying Mechanisms	Reference
1	Rats	cobalt	HIF-1 and HIF-2,	activated	attenuate AKI	apoptosis reduction via regulating mitochondrial pathways	^[14]
	IRPTC,	cobalt	HIF-1	activated	improve IRPTC survival	apoptosis reduction via regulating mitochondrial pathways	^[14]
2	Rats;	Carbon monoxide preconditioning	HIF-1	activated	attenuated AKI	apoptosis reduction	^[16]
	HCK-8 cells	Carbon monoxide preconditioning	HIF-1	activated	reduced apoptosis, increased proliferation	apoptosis reduction	^[16]
3	Mice;	PHD inhibitor FG-4592	HIF-1	activated	attenuated AKI	apoptosis reduction, ameliorated inflammation	^[15]
	HK-2 cells	PHD inhibitor FG-4592	HIF-1	activated	reduced apoptosis	apoptosis reduction, ameliorated inflammation	^[15]
4	Rats	deferiprone	HIF-1	activated	attenuated AKI	reduce apoptosis with increased Mcl1 and survivin expression	^[13]
5	Mice	EC-specific Phd2+/- mice	HIF-1, HIF-2	activated	attenuated AKI	induced antioxidative response	^[18]
6	HK-2 cells	lentivirus-mediated HIF-1α-transfected hASCs	HIF-1	activated	reduced apoptosis and improved cellular morphology	reduced apoptosis	^[19]
7	Mice	lentivirus-mediated HIF-1α-transfected hASCs	HIF-1	activated	attenuated AKI	reduced apoptosis, ameliorated inflammation	^[20]

IRPTC, immortalized rat proximal tubular cells; HCK-8, human renal proximal tubular cell line; HK-2, human proximal tubule epithelial cells; Mcl1, Myeloid cell leukemia-1; EC, endothelial cell; hASCs, Human adipose-derived stem cells.

HIF induction in cisplatin-induced AKI has been reported by several studies though whether cisplatin can directly activate HIF is still controversial. It is possible that in in vitro conditions, the existence of normal oxygen (21% O₂ level usually used for cell cultivation) may prevent HIF activation with cisplatin injury. However, in in vivo conditions, cisplatin-induced vascular damage and renal blood flow reduction may break the balance between low delivery and high consumption of oxygen in renal tubules, leading to severe local hypoxia^[21]. Though with some variations in different in vivo models, HIF is likely activated due to this local hypoxia after cisplatin injury.

Consistently, the protective effect of HIF activation has been reported in several studies , The in vivo and in vitro evidence implicates that HIF up-regulation can be an effective therapeutic strategy for preventing cisplatin-induced AKI. ^[13]^[14]^[15]^[16]^[18]^[19]^[20]. Currently, the underlying mechanism for the reno-protection of HIF in cisplatin induced nephrotoxicity has been explored but not completely understood (Figure 2). In most of the studies, the reduction of renal tubular apoptosis has been reported^[13]. In addition, HIF activation is also associated with anti-oxidative effects, showing less lipid peroxidation^[18], which may be related to ferroptosis inhibition. Furthermore, HIF activation may protect endothelial cells because angiogenesis-related genes such as VEGF may be induced^[19]^[20]. The anti-inflammation effect of HIF activation may also contribute to its reno-protection. HIF upregulation by PHD inhibitor or HIF-1α overexpression can significantly reduce multiple cytokine release after cisplatin injury, which can lead to less inflammatory cell infiltration and reduced renal injury^[15]^[20]. Finally, HIF also interacts with other pathways that are involved in the development and progress of cisplatin-induced AKI, like cell cycle arrest, autophagy. In conclusion, current evidence indicates that HIF activation is beneficial to the kidney during cisplatin chemotherapy. Further investigation on HIF-1 and its interaction with other cellular process may reveal deeper understanding and novel therapeutic targets of cisplatin-induced AKI.

Figure 2. The involvement of HIF in cisplatin-induced nephrotoxicity. During cisplatin chemotherapy, HIF may protect kidneys from AKI and CKD by the inhibition of tubular cell death, the regulation of cell proliferation, the suppression of kidney inflammation, and the attenuation of vascular damage.

3.HIF in Cisplatin-Induced AKI to CKD Progression

Numerous evidences have demonstrated that tubulointerstitial hypoxia is not only an essential contributor to AKI but also a key player in CKD. Chronic hypoxia is considered as a common pathological condition in CKD^[22]^[23]. Though studies have revealed that multiple pathophysiological mechanisms are related to cisplatin-induced AKI to CKD progression ^[7]^[24]^[25]^[26]^[27]^[28], the investigation focusing on the role of HIF in this field is lacking. Nevertheless, HIF is a potential player in this process because of its essential role in hypoxia and its interactions with multiple pathophysiological procedures involved in the progression of CKD such as as tubular cell proliferation, oxidative stress, inflammation and interstitial fibrosis (Figure 2).

4.Therapeutic Potential of HIF in Cisplatin Chemotherapy

In view of the role of HIF in cisplatin-induced nephrotoxicity, targeting or activating HIF and its related pathways may be a therapeutic strategy. PHD-pVHL pathway plays a vital role in HIF regulation, and pharmacological or genetic inhibition of PHD activity is under intensive research in kidney diseases^[15]^[29]^[30]^[31]^[32]^[33]^[34]^[35]^[36][18,45,167,168,181–185]. The role of regulating HIF in cisplatin-induced nephrotoxicity is summarized in Table 1; besides the evidence that HIF accumulation by PHD inhibitors treatment protects against cisplatin-induced nephrotoxicity [^[15]], studies have reported beneficial effects of PHD inhibitors in other kidney diseases including ischemic AKI^[30]^[31], diabetic nephropathy^[33]^[34], obesity related kidney disease^[32], chronic tubulointerstitial nephritis^[35], and remnant kidneys models of CKD^[37]. A great breakthrough in this field is that PHD inhibitors have been proved to have a therapeutic effect in anemia, a complication of CKD that contributes to poor clinical outcome^[38].

Notably, although HIF activation may have protective effect on kidney during cisplatin chemotherapy, it may attenuate the anti-cancer effects of cisplatin in tumors [195]. Studies have revealed HIF overexpression in multiple tumors ^[17]^[39] and found that HIF is closely related to tumor resistance to cisplatin^[40]^[41]^[42]^[43]. More studies showing HIF's involvement in cancers during cisplatin chemotherapy are summarized in Table 2. In general, inhibiting HIF has been shown as a powerful strategy to reinforce anti-cancer efficiency of chemotherapeutic strategies including cisplatin ^[44]^[45]^[46]^[47]. Thus, in cisplatin chemotherapy, activating HIF is a double-edged sword. The failure to balance its effects on cisplatin’s anti-tumor function and nephrotoxicity may limit its application in cisplatin-induced AKI or CKD. Therefore, the clinical application of PHD inhibitors to reduce the side-effect of cisplatin requires further investigation and evaluation.

In conclusion, when considering therapeutic strategies activating or targeting HIF in cisplatin-induced nephrotoxicity, more comprehensive and rigorous work is still needed to identify novel chemicals or drug delivery techniques to achieve the maximal reno-protective effect without diminishing the anti-tumor efficacy of cisplatin.

Table 2. Summary of studies about therapeutic potential of HIF in cisplatin chemotherapy.

Number	Model	Strategies for HIF Regulation	Involved HIF Isoforms	Is HIF Activated or Inhibited	Effects	Underlying Mechanisms	Reference
1	Ovarian cancer cell lines	HIF-1α SiRNA; 1-methyl-1, 9 PA	HIF-1α	inhibited	increased cancer cell sensitivity to cisplatin	Regulation of aerobic glycolysis and mitochondrial oxidative phosphorylation; induced apoptosis through ROS overproduction	^[43]
2	Ovarian cancer cell lines	HIF-1α SiRNA	HIF-1α	inhibited	increased cancer cell sensitivity to cisplatin	Regulation of the interaction between p53 and RAS signaling and dysregulation of apoptosis and autophagy	^[42]
2	mice with ovarian cancer cell tumor xenograft	HIF-1α SiRNA	HIF-1α	inhibited	inhibited tumor growth		^[42]
3	Ovarian cancer cell lines	Topotecan	HIF-1α	inhibited	reversed hypoxia-induced cisplatin and paclitaxel resistance	restored p53 transcriptional activity, downregulated ABCB1/ABCB5 cell surface expression	^[48]
4	Lung adenocarci-noma Cells	HIF-2α SiRNA	HIF-2α	inhibited	increased cancer cell sensitivity to cisplatin	decreased the expression of P-glycoprotein 1	^[49]
5	Human lung adenocarci-noma cell lines	HIF-1α SiRNA	HIF-1α	inhibited	increased cancer cell sensitivity to cisplatin	decreased MDR1 and MRP expression	^[50]
6	Human lung adenocarci-noma cell lines	HIF-1α SiRNA	HIF-1α	inhibited	increased cancer cell sensitivity to cisplatin	Unsure, possibly related to mechanisms other than MDR1 gene regulation	^[51]
7	mice with tumor xenograft from human ESCC cell	HIF-1α SiRNA	HIF-1α	inhibited	inhibited tumor growth	induced cell apoptosis	^[52]
8	Human NSCLC cell lines	Panobinost-at	HIF-1α	inhibited	inhibited cell proliferation and viability; suppressed growth of multicellular spheroids	More chromatin fragmentation and induction of apoptosis	^[53]
9	Human prostate cancer cell	HIF-1α SiRNA	HIF-1α	inhibited	inhibited cell viability, proliferation, and colony formation capability	induced apoptosis through ROS overproduction	^[54]
9	mice with tumor xenograft from human prostate cancer cell	HIF-1α SiRNA	HIF-1α	inhibited	inhibited tumor growth	induced apoptosis through ROS overproduction	^[54]
10	Human NSCLC cell lines	Oroxylin A	HIF-1α	inhibited	increased cancer cell sensitivity to cisplatin	inhibited nucleotide excision repair through suppressing XPC transcription	^[55]
10	mice with tumor xenograft from human NSCLC cell	Oroxylin A	HIF-1α	inhibited	reduced tumor growth		^[55]
11	Human ovarian cancer line	Noscapine	HIF-1α	inhibited	increased cancer cell sensitivity to cisplatin	downregulated HIF-1 transcriptional activity and MDR1 overexpression	^[56]
12	Human NPC cell lines	Evofosfami-de	HIF-1α	inhibited	exhibited hypoxia-selective cytotoxicity and increased cancer cell sensitivity to cisplatin	induced G2 cell cycle arrest and DNA damage	^[57].
12	Tumor-bearing mice with xenograft derived from human NPC cell lines	Evofosfami-de	HIF-1α	inhibited	inhibited tumor growth	induced G2 cell cycle arrest and DNA damage	^[57].
13	Chondrosarcoma cell lines	EPAS1 shRNA	HIF-2α	inhibited	decreased sphere-forming potential, clonogenicity, and proliferative capacity; suppressed cell invasiveness	induced cell apoptosis	^[58]
	Chondrosarcoma cell lines	HIF-2α inhibitor TC-S7009			blocked sphere formation, clonogenicity, invasive phenotypes, and matrix-degrading activity
	Tumor-bearing mice with xenograft derived from chondrosarcoma cell lines	HIF-2α inhibitor TC-S7009			nearly abolished invasive outgrowth and profound suppression of metastasis
14	Tumor-bearing mice with xenograft derived from melanoma cells	EC-specific Phd2+/- mice	HIF-1, HIF-2	activated	normalized tumor vessels; inhibited tumor growth, increased tumor sensitivity to cisplatin	increased vessel perfusion and drug delivery.	^[18]

1-methyl-1, 9 PA, 1-methyl-1, 9-pyrazoloanthrone; ABCB1, ATP Binding Cassette Subfamily B Member 1; ABCB5, ATP Binding Cassette Subfamily B Member 5; MDR1, multidrug resistance-1; MRP, multidrug resistance-associated protein; ESCC, esophagus squamous cell carcinoma; NPC, nasopharyngeal carcinoma; EPAS1, Endothelial PAS Domain Protein 1.

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Zheng Dong

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1. Introduction

References