Dietary Omega-3 Polyunsaturated Fatty Acids and Amelioration of CKD: Possible Cellular Mechanisms

To preserve kidney function for adults with CKD or increased CKD risk, dietary modifications are recommended. Namely, dietary intake of nonsaturated fats, primarily monounsaturated and polyunsaturated lipids, including omega-3 fatty acids, has been recommended in addition to sodium and protein restriction.¹ Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are referred to as essential fatty acids because they are not intrinsically synthesized. Accumulating evidence suggests that omega-3 PUFAs have potential benefits in preserving kidney function in patients with different types of CKD.² Furthermore, omega-3 PUFAs exert pleiotropic biological actions, including lipid-modulating, antihypertensive, antithrombotic, and anti-inflammatory effects, as well as cardiovascular protection.² In addition, a recent pooled analysis of 19 cohorts demonstrated that high levels of seafood-derived omega-3 PUFAs are associated with a reduced CKD risk and a slower decline in kidney function.³

The final common pathway of kidney damage often involves inflammation and tubulointerstitial fibrosis. Consequently, therapies that influence inflammation, such as omega-3 PUFAs, have been assessed. Experimental studies using various models have shown the beneficial effects of omega-3 PUFAs.^4–6 Inflammation involves two processes, initiation and resolution, both of which are active reactions. Omega-6 and omega-3 PUFA-derived metabolites are crucially involved in both processes, and an imbalance in these metabolites leads to the amplification and long-term continuation of inflammation, resulting in tissue damage. Accelerated resolution of inflammation contributes to the maintenance of organ homeostasis. Omega-3 PUFA metabolites promote resolution and protect the kidney from ischemia-reperfusion injury.² Thus, a balanced intake of omega-3 and omega-6 has been suggested to have beneficial implications for kidney health. However, it remains unclear how and to what extent their dietary intake would benefit CKD.

In this issue of Kindey360, Muramatsu et al.⁷ examined whether a diet rich in omega-6 arachidonic acid (ARA) and/or omega-3 docosahexaenoic acid (DHA) mitigated the increase in urinary albumin excretion and renal dysfunction in rats subjected to 5/6 nephrectomy. The rats underwent 5/6 kidney removal and were consistently fed diets containing ARA and/or DHA for 4 weeks. Nephrectomy led to increased levels of urinary albumin excretion, reactive oxygen species, inflammation, and tubule-interstitial fibrosis, all of which were attenuated in rats fed a DHA-containing diet, whereas no such improvement was observed in rats fed ARA− or ARA+ DHA-containing diets.

In addition to confirming the suppressive effects of DHA on nephrectomy-induced inflammation and fibrosis,^4,5 this study explored the possible mechanisms by which DHA protects against kidney fibrosis. This study involved the analysis of fatty acid composition and their metabolites in the kidney using gas chromatography and liquid chromatography-tandem mass spectrometry. Nephrectomy significantly increases ARA and its metabolites, such as thromboxane B2, which acts as a precursor of proinflammatory mediators in the kidney. By contrast, DHA supplementation not only increased the levels of DHA and eicosapentaenoic acid (EPA), along with their metabolites, including 4-hydroxy-docosahexaenoic acid, 20-hydroxy-docosahexaenoic acid, and 18-hydroxyeicosapentaenoic acid, which serve as precursors of proresolution mediators, but also reduced the ARA levels in the kidney. Furthermore, DHA downregulates the expression of proinflammatory cytokines and the infiltration of inflammatory cells into the kidney, leading to the amelioration of renal dysfunction and fibrosis. These results suggest that the alterations induced by DHA in the composition of FAs, particularly the significant reduction in ARA metabolites and increase in DHA and EPA metabolites, may confer beneficial effects on renal function by regulating inflammation.

As an additional cellular mechanism by which DHA impedes CKD progression, this study explored the potential involvement of the uremic toxin indoxyl sulfate (IS) in the kidney. The study observed a noteworthy decrease in IS levels in the kidneys of rats fed the DHA-containing diet. Because IS is a protein-bound uremic toxin, the authors assumed that DHA might act as a competitor for IS binding, thereby enhancing its clearance, reducing its accumulation in proximal tubular epithelial cells (PTECs), and ameliorating IS-induced oxidative stress, thus providing protection against tubular injury. Given that IS directly accelerates cellular senescence in PTECs,⁸ which is associated with tubulointerstitial injury, IS accumulation in the tubules and higher serum IS levels may contribute to a vicious cycle that leads to CKD progression. Further investigations are required to determine whether DHA supplementation directly reduces IS accumulation and tubulotoxicity in the pathogenesis of CKD. Collectively, the authors concluded that dietary intake of DHA can suppress CKD progression, although further mechanistic, epidemiological, and clinical studies are warranted to elucidate the role of omega-3 PUFAs in the prevention and treatment of CKD.

Finally, considering that the macroautophagy/autophagy-lysosomal system plays a primary role in cellular clearance, we would like to introduce the concept of autophagy as another plausible mechanism for the ameliorative effects of omega-3 PUFAs. Recent studies have suggested that autophagy is impaired in various forms of CKD.^9,10 For instance, overloaded lipids, such as saturated palmitic acid, induce autophagy to maintain the integrity of PTECs by renewing the plasma and organelle membranes. However, the activation of autophagy places a burden on the lysosomal system, leading to autophagy stagnation, which manifests as phospholipid accumulation in enlarged lysosomes.¹⁰ Previous findings have demonstrated that EPA reduces several hallmarks of renal lipotoxicity, including both lysosomal and mitochondrial dysfunction, inflammation, and fibrosis. Notably, the efficacy of EPA is not only solely reliant on improvements in metabolic syndrome but also involves various cell-intrinsic and autophagy-dependent mechanisms. EPA ameliorates lysosomal dysfunction and autophagy impairment, reduces the demand for autophagy, and facilitates the formation of lipid droplets, as well as the transfer of fatty acids from lipid droplets to mitochondria for beta-oxidation.⁶ Furthermore, autophagy stagnation is also observed in aging kidneys, where the gradual accumulation of waste impedes autophagy enhancement.⁹ Consequently, omega-3 PUFAs may slow down kidney aging by modulating cellular membranes, thereby improving autophagy.

In conclusion, this study demonstrates that omega-3 PUFAs attenuate fibrosis in animals with CKD by mitigating oxidative stress and inflammation. These observations highlight the potential role of omega-3 PUFAs as adjuncts to therapeutic strategies aimed at retarding the progression of CKD.

Disclosures

Y. Isaka reports the following: Employer: Osaka University Graduate School of Medicine; Consultancy: Kirin Co., Ltd. And Sanwa Kagaku Kenkyusyo Co., Ltd.; Research Funding: Kirin Co., Ltd.; Advisory or Leadership Role: Kirin Co., Ltd. and Sanwa Kagaku Kenkyusyo Co., Ltd.; and Speakers Bureau: Astellas Pharma Inc., AstraZeneca plc, Kirin Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical Co., Ltd., and Sanwa Kagaku Kenkyusyo Co., Ltd. T. Yamamoto reports the following: Employer: Osaka University Graduate School of Medicine; Research Funding and Speakers Bureau: Nippon Boehringer Ingelheim Co., Ltd.

Funding

This work is supported by Japan Society for the Promotion of Science from 23K07671 and Japan Agency for Medical Research and Development from 23ek0310022 (T. Yamamoto).

Author Contributions

Conceptualization: Yoshitaka Isaka, Takeshi Yamamoto.

Writing – original draft: Takeshi Yamamoto.

Writing – review & editing: Yoshitaka Isaka, Takeshi Yamamoto.