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]. 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]. In hypertensive rats, DMOG also reduced glomerulosclerosis, fibrosis and proteinuria [154]. This effect was not observed in DMOG-treated animals lacking endothelial HIF-2 [69]. In the streptozotocin (STZ)-induced diabetic nephropathy rat model, cobalt chloride (CoCl₂), another inhibitor of HIF hydroxylation, improved GFR, albuminuria and tubulointerstitial damage [155]. Additionally, CoCl₂ had a protective effect in the Thy1 nephritis rat model, in the subtotal nephrectomy rat model and in Type 2 diabetic nephropathy [156,157]. 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]. Enoradustat also reduced albuminuria and alleviated renal damage in the diabetic nephropathy ob/ob model [165]. Enoradustat was similarly protective in the rat subtotal nephrectomy model, decreasing fibrosis and inflammation [166].

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]. Schley et al. found that HIF-PHIs cause renal mononuclear phagocytes to adopt an anti-inflammatory phenotype [168]. 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]. Genetic endothelial-specific knockout of PHD2 (leading to constitutive HIF-1α and HIF-2α stabilization) also induced fibrosis and worsened kidney damage [121]. Similarly, genetic HIF-2a overexpression in the tubules exacerbated renal fibrosis [170]. 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]. 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]. Blocking PKCα signaling with the chemical inhibitor Go6976 also inhibited fibroblast activation and renal fibrosis [175]. 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].

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]. 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]. 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].

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]. Additionally, promoting mitochondrial biosynthesis is a promising approach to block AKI to CKD progression [183]. In several AKI models, resveratrol (an SIRT1 agonist) and AICAR (an AMPK agonist) improved mitochondrial fitness and protected from renal fibrosis [184,185]. 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]. Enhancing mitophagy in TECs is also an effective strategy to treat AKI to CKD progression [115]. Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, reduced cisplatin-induced TEC cytotoxicity by inducing mitophagy through the PINK1/Parkin signaling pathway [187]. 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]. 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]. 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]. 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]. 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]. That is the case of allopurinol, which slows down renal disease progression in CKD patients [194]. 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]. Oral administration of APX-115, a pan-inhibitor of NOX enzymes, reduced fibrosis in the murine model of STZ-induced kidney disease [196]. Setanaxib (GKT137831), a first-in-class, dual inhibitor of NOX1/4, also showed renoprotective effects in this model [197]. Treatment of db/db mice with GKT136901, a NOX1/NOX4 inhibitor, blocked renal NOX4-dependent fibrotic signaling after exposure to high glucose [198]. Of note, H₂S 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]. Vitamin E reduced cardiovascular disease and myocardial infarction events in hemodialysis patients [201]. A moderate dose of Vitamin C might be beneficial for CKD patients with iron deficiency [202]. CoQ10 supplementation restored the metabolic profile of CKD patients [203]. 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]. Plant-derived polyphenols, such as quercetin, curcumin and resveratrol, have also emerged as promising antioxidant agents with renoprotective effects [206]. Rassaf et al. discovered that supplementation with cocoa flavanol resulted in a reduction in endothelial dysfunction in ESRD patients [207]. However, well-powered clinical studies are still needed to obtain a meaningful evaluation of the effects of Nrf2 system-targeting compounds.