Chronic kidney disease (CKD) affects 10% of the population. Fibrosis is the hallmark of CKD, which is marked by the deposit of extracellular matrix (ECM). This response is the final outcome of an unbalanced reaction to inflammation and wound healing and can be induced by a variety of insults, including hypoxia. Vascular damage results in an impaired tissue oxygen supply, inducing immune cell infiltration, tubule injury and the activation of ECM-secreting myofibroblasts. In turn, tubulointerstitial fibrosis development worsens oxygen diffusion. Hypoxia-inducible factor (HIF) is the primary transcriptional regulator of hypoxia-associated responses, such as oxidative stress and metabolic reprogramming, triggering a proinflammatory and profibrotic landscape.
Chronic kidney disease (CKD) is a clinical setting with a gradual decline in renal function. It has high rates of morbidity and mortality and constitutes a significant medical, social and economic burden. It affects about 10% of the global population and affects roughly 30–40% of patients with high prevalent pathologies, such as diabetes mellitus and hypertension
[1]. Acute kidney injury (AKI) is a risk factor for developing CKD, whereas CKD sensitizes patients to AKI
[2]. While a lot has been learned about the mechanisms underlying these diseases, the causes predisposing AKI to CKD and vice versa remain largely elusive. High rates of cardiac diseases are reported in CKD patients with chronic inflammation, which may result in a reduced blood supply to the kidneys
[3]. Dysregulation of the immune system following AKI could be a major factor contributing to increased risk of CKD based on the incomplete tissue relocation of immune cells after injury
[4,5][4][5]. Genetic conditions such as polycystic kidney disease (PKD), immune glomerulopathies and exposure to environmental chemicals are less frequent causes of CKD. Within the next 20 years, CKD is ranked to be the fifth leading cause of death worldwide
[6]. Although multiple interventions have been used to slow the progression of CKD, including strict control of blood pressure and glycaemia, correction of dyslipidemia, halting of potentially nephrotoxic drugs or smoking, blockade of the renin-angiotensin system to lower glomerular capillary pressure and immunosuppression in some rapidly progressing disorders, none of the current tactics have shown effectiveness to revert the progression to end-stage renal disease (ESRD). Sodium-glucose cotransporter-2 (SGLT2) inhibition showed promising in recent trials. However, most of CKD patients advance toward ESRD, which requires dialysis or kidney transplant
[7].
Nephrons are the functional units of the kidney, formed by glomeruli and tubules. The glomerulus retains cells and big proteins while filtering the blood. The filtrate enters the tubule to produce the final urine by eliminating or adding substances to the tubular fluid. Kidneys keep the interior environment in a state of homeostasis by maintaining the proper balance of water, minerals, electrolytes and hydrogen ions as well as removing toxins. That is the case of uremic toxins, substances produced by protein metabolism that accumulate in patients with impaired renal function, contributing to CKD progression. Many of these protein-bound uremic toxins are gut-derived from the degradation of aromatic amino acids by intestinal bacteria. The most-studied ones are p-cresol, p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, indole-3-acetic acid, trimethylamine-N-oxide, phenylacetylglutamine and hippuric acid
[8]. Regardless of etiology, CKD progression involves the development of tubulointerstitial and glomerular fibrosis. It involves the excessive accumulation of extracellular matrix proteins (ECM), such as fibronectin, proteoglycans and collagens, which replace the cellular living tissue. This is the result of an unbalanced response to inflammation and wound healing that activates ECM-secreting myofibroblasts
[9].
Renal injury, caused by toxic compounds, hypoxia or proteinuria, promotes rarefaction of the peritubular microvasculature and damages the tubular epithelium, which leads to its subsequent dedifferentiation or cell death. Reduced number of functional nephrons results in hyperfiltration by the remnant kidney, increasing biomechanical forces that can determine cellular injury. The responses underlying tubular damage are complex, involving oxidative stress, metabolic alterations, cell cycle arrest, dedifferentiation, senescence, inflammatory mediators and epigenetic changes. After the first insult, the remaining cells go through a recovery phase during which regeneration mechanisms are activated to restore epithelial cell characteristics and functions. An incomplete repair promotes fibrosis and CKD progression. By secreting paracrine proinflammatory or profibrotic mediators, sublethal injured tubular epithelial cells (TECs) can act as fibrogenesis initiators
[10]. The main profibrogenic cytokine is Transforming growth factor-β (TGF-β)
[11]. In addition to a variety of cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor (TNF), other key fibrogenic factors include platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), fibroblast growth factor 2 (FGF2), tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and angiotensin II (Ang II)
[12], triggering the activation of TGF-β, Notch, Wnt/β-Catenin, PDGF and Ang II/Reactive oxygen species (ROS)-signaling pathways. These proinflammatory/profibrotic factors are crucial for kidney fibrosis development by triggering ECM-producing myofibroblast activation, epithelial cell dedifferentiation/apoptosis and inflammatory cell recruitment/activation, perpetuating the fibrotic loop.
2. Hypoxia as a Therapeutic Target in Chronic Kidney Disease
Given that renal hypoxia is a final common path in CKD development and that the genetic suppression of the HIF pathway aggravates renal injury, HIF activation/stabilization is suggested as a potential therapy for CKD
[152][13]. Dimethyloxalylglycine (DMOG), a competitive inhibitor of HIF-alpha prolyl hydroxylase (HIF-PH), improved proteinuria, mitochondrial function and cell survival in the rat subtotal nephrectomy model
[153][14]. In hypertensive rats, DMOG also reduced glomerulosclerosis, fibrosis and proteinuria
[154][15]. This effect was not observed in DMOG-treated animals lacking endothelial HIF-2
[69][16]. In the streptozotocin (STZ)-induced diabetic nephropathy rat model, cobalt chloride (CoCl
2), another inhibitor of HIF hydroxylation, improved GFR, albuminuria and tubulointerstitial damage
[155][17]. Additionally, CoCl
2 had a protective effect in the Thy1 nephritis rat model, in the subtotal nephrectomy rat model and in Type 2 diabetic nephropathy
[156,157][18][19]. Beside the beneficial effects of cobalt in experimental animals, long-term administration to humans has adverse effects. In this regard, the new HIF-PHD inhibitors (HIF-PHIs) roxadustat, daprodustat, vadadustat and enarodustat improved renal anemia and exerted a positive effect on the hemoglobin rate in CKD patients
[158,159,160,161,162,163,164][20][21][22][23][24][25][26]. Enoradustat also reduced albuminuria and alleviated renal damage in the diabetic nephropathy ob/ob model
[165][27]. Enoradustat was similarly protective in the rat subtotal nephrectomy model, decreasing fibrosis and inflammation
[166][28].
While the pre-stimulation of the HIF pathway both genetically and pharmacologically reduces AKI episodes, its beneficial role in CKD progression is still controversial and mainly relies on pre-ischemic activation
[167][29]. Schley et al. found that HIF-PHIs cause renal mononuclear phagocytes to adopt an anti-inflammatory phenotype
[168][30]. By contrast, some other CKD preclinical studies showed that HIF-signaling activation in the kidney appears to be deleterious, as evidenced the stabilization of HIF-1 by genetic deletion of VHL in a 5/6 renal ablation model and the administration of an anti-HIF-1α drug in the UUO model
[169][31]. Genetic endothelial-specific knockout of PHD2 (leading to constitutive HIF-1α and HIF-2α stabilization) also induced fibrosis and worsened kidney damage
[121][32]. Similarly, genetic HIF-2a overexpression in the tubules exacerbated renal fibrosis
[170][33]. Therefore, the role of HIF activation is likely to depend on the pathological context, cell type and timing. Additional investigation is necessary to clarify the implications and mechanisms of HIF-PHIs on CKD progression.
Strategies directed towards the preservation of peritubular capillaries early in the AKI process lead to maintaining renal oxygen levels and exert a protecting role in AKI to CKD transition. Thus, treatment with the angiogenic factors VEGF-121 or angiopoietin-1 administered early during injury suppressed AKI to CKD transition in the IRI model, by attenuating the loss of peritubular capillaries and subsequent tubulointerstitial fibrosis
[171,172,173][34][35][36]. Protein kinase C comprises a superfamily of serine-threonine kinases with diverse functions in signal transduction and cellular regulation. Inactivation of PKC isoforms were shown to alleviate many diabetes- or hyperglycemia-associated vascular dysfunctions in the kidney
[174][37]. Blocking PKCα signaling with the chemical inhibitor Go6976 also inhibited fibroblast activation and renal fibrosis
[175][38]. Targeting fibrosis has been mainly addressed by blocking the TGF-β signaling pathway. It includes several strategies including Smad agonists/inhibitors and neutralizing antibodies against receptors/cytokines. However, the pleotropic nature of this pathway has limited their application due to potential side effects
[176][39].
SGLT2 inhibitors (SGLT2is), a new class of antihyperglycemic drugs which act by targeting glucose reabsorption, also lessen principal kidney and cardiovascular problems in CKD patients
[177][40]. Studies have suggested that SGLT2i may reduce cortical oxygen consumption. Reduced oxygen pressure could activate the HIF-signaling pathway and imitate systemic hypoxia
[178,179][41][42]. In the IRI model, SGLT2i was also discovered to prevent renal capillary rarefaction and subsequent hypoxia and fibrosis. However, further research is required to decipher the renoprotective mechanisms of SGLT2 inhibition associated with tissue oxygenation
[180][43].
Multiple substances directed to target mitochondria and correct imbalanced bioenergetics seem to prevent CKD progression. The PPARα agonists fenofibrate and clofibrate attenuated acute renal tubule injury by increasing FAO rate and inhibiting nuclear factor kappa-B (NF-κB) activity, oxidative stress, cellular apoptosis and fibrosis
[181,182][44][45]. Additionally, promoting mitochondrial biosynthesis is a promising approach to block AKI to CKD progression
[183][46]. In several AKI models, resveratrol (an SIRT1 agonist) and AICAR (an AMPK agonist) improved mitochondrial fitness and protected from renal fibrosis
[184,185][47][48]. Mdivi-1, an inhibitor of mitochondrial fission protein DRP1, exerts a beneficial effect in several kidney diseases, attenuating tubular cell apoptosis and maintaining mitochondrial structure
[186][49]. Enhancing mitophagy in TECs is also an effective strategy to treat AKI to CKD progression
[115][50]. Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, reduced cisplatin-induced TEC cytotoxicity by inducing mitophagy through the PINK1/Parkin signaling pathway
[187][51]. Finally, a novel mitochondrial protectant, SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2), specifically binds to cardiolipin in the mitochondrial inner membrane to stabilize the mitochondrial structure, reducing ROS production. It was shown to prevent tubular apoptosis, interstitial fibrosis and glomerulosclerosis
[188,189][52][53]. Although early restoration of TEC metabolism offers a promising therapeutic approach for AKI, the translation of drugs that target mitochondria and bioenergetics into the clinic is limited due to adverse off-target effects
[190][54]. In addition, available studies have focused only on TECs, so whether other renal cell types undergo metabolic changes needs to be further explored.
Targeting hypoxia-associated oxidative stress in CKD using antioxidants has also emerged as a potential therapeutic strategy. Nrf2–ARE axis activation triggers strong antioxidative effects
[191][55]. Therefore, the pharmacological stimulation of this system may be a promising target. Bardoxolone methyl, a Nrf2 activator that inhibits Keap1 through modifying Keap1-cysteine-151, was reported to increase glomerular filtration rate (GFR) in diabetic CKD patients on different clinical trials
[192][56]. Inhibitors of xanthine oxidase, an enzyme involved in purine catabolism producing ROS, ameliorate renal damage and reduce uric acid levels, proinflammatory mediators and ROS
[193][57]. That is the case of allopurinol, which slows down renal disease progression in CKD patients
[194][58]. The inhibition of NOX enzymes has emerged as a promising approach to target ROS. Although NOX2 is also expressed, NOX4 is the most prevalent type in the kidney.
[195][59]. Oral administration of APX-115, a pan-inhibitor of NOX enzymes, reduced fibrosis in the murine model of STZ-induced kidney disease
[196][60]. Setanaxib (GKT137831), a first-in-class, dual inhibitor of NOX1/4, also showed renoprotective effects in this model
[197][61]. Treatment of db/db mice with GKT136901, a NOX1/NOX4 inhibitor, blocked renal NOX4-dependent fibrotic signaling after exposure to high glucose
[198][62]. Of note, H
2S donors, such as sodium thiosulfate, maintain redox homeostasis by ROS scavenging and modifying cysteine residues on key signaling molecules, which exerts renal protection
[199,200][63][64]. Vitamin E reduced cardiovascular disease and myocardial infarction events in hemodialysis patients
[201][65]. A moderate dose of Vitamin C might be beneficial for CKD patients with iron deficiency
[202][66]. CoQ10 supplementation restored the metabolic profile of CKD patients
[203][67]. In renal IRI and Ang II-infused mouse models, pre-administration of MitoQ reduced oxidative damage and apoptosis by reducing aberrant mitochondrial fission and restoring mitophagy by activating the NRF2 pathway
[204,205][68][69]. Plant-derived polyphenols, such as quercetin, curcumin and resveratrol, have also emerged as promising antioxidant agents with renoprotective effects
[206][70]. Rassaf et al. discovered that supplementation with cocoa flavanol resulted in a reduction in endothelial dysfunction in ESRD patients
[207][71]. However, well-powered clinical studies are still needed to obtain a meaningful evaluation of the effects of Nrf2 system-targeting compounds.
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