Renal-Protective Roles Of Lipoic Acid in Kidney Disease Ⅱ

4. Miscellaneous 

1. Aging is linked to functional decline in the kidneys [132,133]. It has been established that there are numerous changes in the molecular, structural, and morphological levels in the kidney [134,135]. In aging kidneys, there are increased levels of oxidative stress, as reflected by increased lipid peroxidation, mitochondrial dysfunction, and decreased levels of antioxidants, including superoxide dismutase, catalase, and glutathione peroxidase [136–139]. Not surprisingly, ALA could alleviate all of these deleterious changes in aged kidneys [136–138]. Additionally, ALA given as a dietary supplement has been shown to be able to reverse age-related decline in kidney function and serum total proteins [140]. These studies demonstrate the protective and preventative effects of ALA on kidney aging.

CLICK HERE TO GET CISTANCHE FOR CKD TREATMENTS

2. Sleep apnea is a disorder that causes intermittent hypoxia, which can further cause hypoxia-associated renal injury [141–144]. ALA has been found to be protective against renal injury induced by sleep apnea hypoxia [145]. In a study using a mouse model of sleep apnea, Abuyassin et al. have demonstrated that in the animals that underwent intermittent hypoxia and were treated with an ALA-enhanced diet, renal oxidative stress and inflflammation were lower than those exposed to intermittent hypoxia only. Moreover, renal cell death and tubular injury were also deceased in the intermittent hypoxia + ALA group, and treatment with ALA mitigated intermittent hypoxia-induced glomerular hypertrophy and decreased albuminuria [145]. Therefore, ALA is nephroprotective in hypoxia-related kidney injury induced by sleep apnea. 

3. Functional impairment of the kidneys is also a frequent disorder in the presence of high blood pressure, also known as hypertension. It has been thought that renal damage linked to hypertension is caused by oxidative stress [146–148]. In this regard, ALA has also been tested for its antioxidant role in hypertension-induced kidney injury. Martinelli et al. [149] have found that when spontaneous hypertensive rats with high blood pressure were treated by a racemic mixture of ALA, renal oxidative damage was attenuated, with a signifificant improvement in kidney function accompanied by ameliorated glomerular and tubular injury. This study also indicates that when exogenous ALA is administered, a racemic mixture of ALA is often used [149].

4. Chronic kidney disease (CKD) can be created by feeding animals with a high concentration of adenine [150–152]. In fact, adenine-induced CKD is a popular model for studying the pathophysiology of chronic kidney injury and the therapeutic effects of a variety of natural products or drugs [153–155]. Nonetheless, the nephroprotective role of ALA has not been comprehensively evaluated in this animal model, which should be investigated in the future. Additionally, the protective effects of ALA on each of the five stages of chronic kidney disease [156–158] should also be studied in this animal model of CKD. 

5. IgA nephropathy (IgAN) is known to cause glomerulonephritis due to the deposition of IgA 1 [159–161] and is a prevalent chronic kidney disease [162–164]. Its major feature is mesangial cells and mononuclear leukocyte infiltration in renal interstitial tissues and the glomerulus. It has been demonstrated that oxidative stress-induced protein oxidation and lipid peroxidation is some of the underlying pathogenic mechanisms [165–169]. While animal models of IgAN are available for studying the pathogenesis of IgAN and exploring therapeutic approaches [170,171], the potential effects of ALA in this kidney disorder have not been evaluated. Nonetheless, it is conceivable that ALA would exhibit nephroprotective effects in IgAN, given its powerful antioxidant capacity.

6. It is also worth noting that studies comparing the renoprotective effect of ALA with other agents have also been conducted in recent years. For example, ALA was compared with a traditional Chinese medicine Huangkui capsule in rats with diabetic nephropathy [172]. The authors found that ALA is equivalent to the Huangkui capsule in renoprotection against diabetic kidney injury, and both agents improve kidney function by attenuating oxidative stress and downregulating the activation of the p38MAPK and Akt pathways. ALA has also been compared with N-acetylcysteine (NAC) in one study, whereby the authors found that NAC is better than ALA in protecting oxidative kidney injury induced by the chemotherapeutic drug ifosfamide, which is highly toxic to the kidney [173–176]. However, the authors used an NAC concentration (200 mg/kg) that was twice that of ALA (100 mg/kg) [176]. Hence, the conclusion that NAC is more renoprotective than ALA in this animal model of kidney injury may not be definitive. It should also be noted that a recent report indicates that ALA can also minimize renal toxicity induced by gold nanoparticles, which are often used as drug carriers [177]. In fact, poly(lipoic acid) nanoparticles themselves can also be used as a therapeutic tool for delivering active compounds [178]. 

5. Summary

In this article, we have reviewed the protective mechanisms of ALA in various animal models of kidney injury. These models cover both AKI and CKD, which include DKD, ischemia-reperfusion-induced kidney injury, sepsis-induced kidney injury, and kidney disorders induced by UUO, cisplatin, cadmium, folic acid, and iron. Common underlying mechanisms of ALA’s renoprotection are summarized in Figure 7. 

Figure 7. Mechanisms underlying lipoic acid’s role in various animal models of kidney injury are discussed in the text. Lipoic acid alleviates kidney injury and improves kidney function by exerting various biological actions, as depicted in this figure.

As further summarized in Table 1, these mechanisms include decreasing oxidative stress, increasing endogenous antioxidant defense capacities, counteracting inflflammation by inhibiting NF-kB and release of inflflammatory cytokines, mitigating renal fibrosis, and decreasing cell death, such as apoptosis, ferroptosis, and necrosis. The eventual outcome of ALA treatment, regardless of the kidney injury models and the protective mechanisms unraveled, is the improvement of kidney function. Therefore, ALA is a promising agent targeting kidney disorders. 

Table 1. Mechanisms of ALA’s renal protection in various animal models of kidney injury are discussed in this review. 

6. Future Perspectives 

Most studies discussed in this review article utilized systemic administration of ALA in their studies of the protective effects of ALA on the respective animal models of kidney injury. Systemic administration of ALA will certainly result in the distribution of ALA to the organs or tissues that may not need ALA, whereby excess ALA may pose deleterious effects [59]. Therefore, future studies will need to focus on developing approaches by which ALA will only be delivered to the kidneys. Such studies of target delivery of ALA to the kidney will certainly provide more insights into the protective mechanisms of ALA in different kidney injury models, elucidating both redox- and energy-modulatory properties of ALA. In this regard, nanoparticle delivery or nanomedicines of ALA targeting the kidney could be a promising approach [179–184]. Additionally, the combination of ALA with other natural products in treating kidney injuries and preventing the AKI to CKD transition will be interesting to investigate. Moreover, comprehensive preclinical and human studies are needed to evaluate the efficacy of ALA in the settings of AKI and CKD, as well as the AKI to CKD transition. 

Author Contributions: Conceptualization, S.F.K. and L.-J.Y.; original draft preparation, S.F.K.; review and editing, J.L. and L.-J.Y. All authors have read and agreed to the published version of the manuscript. 

Funding: Jiankang Liu was supported by the National Natural Science Foundation of China Integrated Project of the Major Research Plan 92249303 and General Projects 32171102 and 31770917. 

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable. 

Data Availability Statement: Not applicable. 

Conflicts of Interest: The authors declare no conflict of interest. 

References 

1. Rennke, H.G.; Denker, B.M. Renal Pathology: The Essentials, 5th ed.; Wolters Kluwer: New York, NY, USA, 2020. 

2. Koeppen, B.M.; Stanton, B.A. Renal Physiology, 5th ed.; Elsevier: Philadelphia, PA, USA, 2013. 

3. Dipiro, J.T.; Talbet, R.L.; Yee, G.C.; Matzke, G.R.; Wells, B.G.; Posey, L.M. Pharmacotherapy: A Pathophysiological Approach, 9th ed.; McGraw-Hill Education: New York, NY, USA, 2014.

4. Lieberman, M.; Marks, A.D. Marks’ Basic Medical Biochemistry: A Clinical Approach, 4th ed.; Wolters Kluwer/Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2013. 

5. Ammirati, A.L. Chronic kidney disease. Rev. Assoc. Med. Bras. (1992) 2020, 66 (Suppl. S1), s03–s09. [CrossRef] [PubMed] 

6. Turgut, F.; Awad, A.S.; Abdel-Rahman, E.M. Acute kidney injury: Medical causes and pathogenesis. J. Clin. Med. 2023, 12, 375. [CrossRef] [PubMed] 7. Duann, P.; Lin, P.H. Mitochondria damage and kidney disease. Adv. Exp. Med. Biol. 2017, 982, 529–551. [PubMed] 

8. Sanz, A.B.; Sanchez-Nino, M.D.; Ramos, A.M.; Ortiz, A. Regulated cell death pathways in kidney disease. Nat. Rev. Nephrol. 2023, 1–19. [CrossRef] 

9. Levey, A.S.; Becker, C.; Inker, L.A. Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: A systematic review. JAMA 2015, 313, 837–846. [CrossRef] 

10. Mima, A. A narrative review of diabetic kidney disease: Previous and current evidence-based therapeutic approaches. Adv. Ther. 2022, 39, 3488–3500. [CrossRef]

Supportive Service:

Email:wallence.suen@wecistanche.com 

Whatsapp/Tel:+86 15292862950

Shop:

https://www.xjcistanche.com/cistanche-shop