Dyslipidemia is a major risk factor of atherosclerotic heart disease in patients with CKD. It has been postulated that the association between dyslipidemia and CKD is not solely a result of epidemiological comorbidities but rather a complex interplay of causality, where CKD exacerbates dyslipidemia, while dyslipidemia, in turn, contributes to the onset and progression of CKD (Harper and Jacobson, 2008; Cases and Coll, 2005). Since Moorhead et al. proposed the lipid nephrotoxicity hypothesis in 1982 (Moorhead et al., 1982), accumulating evidence has suggested that increased plasma lipid levels contribute to the development of renal glomerular and tubular damage, primarily in animal models of dyslipidemia (Ruan et al., 2009). The etiology of dyslipidemia-induced nephrotoxicity is complex and multifaceted, potentially involving the activation of certain cellular signaling pathways that culminate in renal injury through elevated levels of oxLDL (Bussolati et al., 2005; Dai et al., 2014; Deng et al., 2016; Gai et al., 2019). The lectin-like oxLDL receptor, LOX-1, is implicated in organ damage caused by dyslipidemia, and its expression is increased in hypertensive glomerulosclerosis (Nagase et al., 2000). In murine models, a deficiency of LOX-1 leads to a reduction in renal dysfunction, which was precipitated by a systemic inflammatory state following significant myocardial ischemia and injury (Lu et al., 2012). This supports the hypothesis that LOX-1 plays a role in the development of inflammation-induced renal injury. However, to date, no studies have investigated the role of LOX-1 in nephrotoxicity caused by dyslipidemia.

Hypertension is an established risk factor for CKD, and it has been suggested that hypertension and dyslipidemia act synergistically to induce renal dysfunction (Mänttäri et al., 1995). The development of renal damage due to hypertension involves direct renal injury by vasoactive hormones, such as Ang II in addition to renal hemodynamic abnormalities associated with elevated body pressure (Brewster and Perazella, 2004). We have shown that LOX-1 and the Ang II type 1 receptor (AT1) of the G protein-coupled receptor (GPCR) are coupled on the plasma membrane, and that G protein-dependent and β-arrestin-dependent AT1 activation mechanisms are involved in the signaling mechanism by oxLDL and the intracellular uptake of oxLDL, respectively (Yamamoto et al., 2015; Takahashi et al., 2021).

Interestingly, it was recently demonstrated that AT1 exhibits different modes and degrees of G protein activation depending on the conformational changes that occur during activation by various ligands (Wingler et al., 2019). Specifically, G protein αq subunit (Gq)-biased agonists induce a more open conformation of AT1 than Ang II, resulting in a more potent activation of Gq, which is the primary mediator of Ang II-induced hypertension. In contrast, β-arrestin-biased agonists induce a closer conformational change, leading to the activation of β-arrestin without the activation of Gq (Wingler et al., 2019). Indeed, we found that oxLDL selectively activates G protein αi subunit (Gi) of AT1, without activating Gq (Takahashi et al., 2021), similar to that induced by β-arrestin-biased agonists (Namkung et al., 2018). However, given that Ang II and oxLDL coexist in physiological environments, it is plausible to hypothesize that the effect of these ligands on AT1 in living organisms may differ from their effects when administered individually. Indeed, we found that the combination treatment of oxLDL and Ang II enhanced pro-inflammatory NFκB activity compared to each treatment alone in cells overexpressing both AT1 and LOX-1 (Takahashi et al., 2021). Based on our findings and the aforementioned structure-activity relationship of AT1, we hypothesized that the binding of both oxLDL and Ang II to LOX-1 and AT1, respectively, may result in a more open AT1 structure, leading to stronger downstream Gq signaling. Therefore, this study aimed to investigate and clarify this hypothesis, focusing specifically on renal component cells, and ultimately demonstrate the in vivo relevance of this phenomenon in the development of renal injury or renal dysfunction under conditions of Ang II and oxLDL overload.

We conducted a series of experiments to provide empirical support for our hypotheses. We propose that the simultaneous binding of Ang II to AT1 and oxLDL to LOX-1 triggers distinct and more pronounced structural modifications in AT1 than the individual modifications induced by each ligand. This structural alteration in AT1 leads to the enhanced activation of Gq signaling.

To confirm AT1 and LOX-1 colocalization and interaction at the cell membrane, our previous study used in situ proximity ligation assays (PLA) and membrane protein immunoprecipitation assays in CHO cells expressing tagged AT1 and LOX-1, successfully demonstrating AT1/LOX-1 complex formation (Yamamoto et al., 2015). Additionally, we provided histological evidence of their co-localization with megalin in proximal renal tubules to support these findings, although the limitation remains regarding the lack of direct in vivo evidence for membrane co-localization of LOX-1 and AT1. While additional co-staining with other markers to identify specific cell types was not conducted, the prominent localization of AT1R with megalin in our study provides strong evidence of its expression in proximal renal tubules, consistent with established findings regarding AT1R presence in this nephron segment. Previous studies have documented AT1R expression in various renal cells, including mesangial, interstitial, and juxtaglomerular (JG) cells, as well as proximal tubules. In our immunofluorescence analysis, however, we did not observe significant AT1R expression in the glomerulus or mesangium. The pronounced expression of AT1R in proximal tubules aligns with previous reports (Arthur et al., 2021), though limitations in immunofluorescence sensitivity do not exclude AT1R presence in other compartments. Notably, our focus on proximal tubules enabled clear observation of AT1/LOX-1 co-localization, especially under oxLDL and AngII stimulation. This interaction underscores a potential focal point for AT1R/LOX-1 signaling in kidney disease pathogenesis within the renal system.

At the cellular level, live imaging analysis (Figure 2—figure supplement 1) displayed a limited number of overlapping LOX-1 and AT1R puncta, which could be attributed to the dynamic and transient nature of the LOX-1 and AT1 receptor interaction. As described in our previous study (Yamamoto et al., 2015), this interaction is sensitive to buffer conditions, with complex formation occurring under non-reducing but not reducing conditions. This indicates that the LOX-1 and AT1 interaction is mediated by non-covalent rather than stable covalent bonds, leading these receptors to form and dissociate rapidly. Consequently, only a small fraction of LOX-1 and AT1 receptors may be co-localized at any given time point, explaining the limited number of overlapping puncta observed in live imaging. Importantly, despite this limited spatial overlap, our findings indicate that co-treatment with oxLDL and Ang II significantly enhances Gq signaling. This highlights that the functional impact of the LOX-1/AT1 interaction, especially in response to specific stimuli like oxLDL and Ang II, is more crucial to downstream signaling outcomes than the extent of stable receptor co-localization.

The current experiments showed that oxLDL enhanced the effects of Ang II-induced production of IP1, a downstream signaling molecule associated with Gq activation and subsequent calcium influx, further supporting functional activation of the AT1/LOX-1 complex. However, this effect was observed only in the presence of both LOX-1 and AT1. The differences in activation levels observed between the IP1 assay and the calcium influx assay, both indicators of Gq activity, likely arise due to variations in assay sensitivity. While the absolute differences in the IP1 assay between treatment groups may appear modest, the critical comparison between Ang II alone and Ang II with oxLDL consistently demonstrated significant differences, in alignment with the calcium influx results. Notably, co-treatment with oxLDL reduced the EC50 for IP1 production by 80% compared to Ang II alone, underscoring a robust enhancement of Gq signaling, even though the IP1 assay differences were relatively small in absolute terms.

Considering that oxLDL selectively activates Gi but not Gq through the LOX-1-AT1 dependent pathway (Takahashi et al., 2021), it is evident that the observed phenomenon cannot be attributed solely to the additive effect of oxLDL on AT1 activation. Rather, the simultaneous binding of oxLDL and Ang II to their respective receptors, LOX-1 and AT1, which form a single complex, underlies this phenomenon. Indeed, our findings from live imaging of the membrane receptors revealed that the combination of Ang II and oxLDL did not induce any additional influence on the internalization of both receptors upon AT1-β-arrestin activation compared to each ligand alone, suggesting that the quantity of activated receptors is not affected by the combination treatments. Considering the conformation-activation relationship in AT1 activation (Devost et al., 2017), this supports the hypothesis that the simultaneous binding of Ang II and oxLDL in a single AT1-LOX-1 complex induces a greater conformational change, resulting in a more open conformation of AT1 compared with each ligand alone. However, it is technically challenging to directly identify structural modifications of the receptor complex using techniques such as crystal structure analysis. Instead, we utilized AT1 conformational sensors capable of differentiating between the conformational changes induced by Ang II and biased AT1 (Devost et al., 2017). Interestingly, we observed that one of the two conformational sensors employed in this study detected an augmented response in the presence of the combination treatment compared with Ang II alone. Importantly, this enhanced response was significantly inhibited when an LOX-1 antibody was introduced, indicating the dependency of LOX-1 on this phenomenon. These results indicate that the combined treatment with Ang II and oxLDL in the presence of LOX-1 induces a unique conformational change in individual AT1 molecules, which differs from the conformational changes induced by each single treatment alone.

It is important to note that the ability of LOX-1 ligands to enhance Ang II-AT1 signaling is not commonly observed. This was corroborated by the observation that BSA-conjugated AGE, a recognized ligand of LOX-1 (Lymperopoulos et al., 2021), failed to augment the production of IP1 by Ang II compared to control BSA (Figure 1d). While the exact reason for this discrepancy is not yet understood, it is noteworthy that the predicted particle size of oxLDL (Ohki et al., 2005) is significantly larger at 250 Å compared to the maximum particle size of AGE-BSA (Wright and Thompson, 1975), which is 120 Å. This suggests a potentially greater impact of oxLDL on the structural modifications within the AT1-LOX-1 complex. However, further structural analysis is required to validate this hypothesis.

Notably, the Gq bias resulting from combination treatment varied across the mammalian cells examined. Specifically, we observed a combinatorial effect exclusively in renal epithelial and fibroblasts, whereas vascular endothelial and smooth muscle cells did not display the same response. In these renal cells, we observed increased Gq signaling, along with other cellular phenomena such as calcium influx, changes in gene expression, and alterations in cellular characteristics, including myofibroblast activation and cell proliferation. While our study demonstrates a significant upregulation of α-SMA, a well-established marker of myofibroblast, in renal epithelial and fibroblast cells exposed to combined Ang II and oxLDL treatment, we acknowledge the evolving understanding of EMT, particularly the role of partial epithelial-mesenchymal transition (pEMT) in CKD. Notably, pEMT has garnered attention under conditions of inflammation, oxidative stress, and elevated TGF-β, which are also relevant to our Ang II and HFD models. Unlike full EMT, where epithelial cells completely transition into mesenchymal cells, pEMT represents a state in which epithelial cells partially acquire mesenchymal characteristics, such as increased α-SMA expression and the secretion of pro-fibrotic cytokines, while remaining attached to the basement membrane without fully transitioning into fibroblasts (Sheng and Zhuang, 2020). Importantly, previous studies using the unilateral ureteral obstruction (UUO) model suggest that full EMT is unlikely to play a significant role in renal fibrosis and that most kidney fibroblasts are thought to originate from interstitial cells rather than via EMT (Kriz et al., 2011). The observed increase in α-SMA in our model may, therefore, indicate a pEMT-like state, indirectly contributing to fibrosis by promoting cytokine and growth factor release rather than directly driving fibroblast generation. This interpretation aligns with findings from other kidney fibrosis models, including the UUO model, which shares pathophysiological features such as inflammation and oxidative stress with our model. Given these considerations, the increased α-SMA expression observed in our study may be indicative of pEMT rather than definitive evidence of EMT directly contributing to fibroblast differentiation. Additionally, extrapolating in vitro pEMT findings to in vivo models presents inherent challenges, as detecting these subtle phenotypic changes remains complex (Hadpech and Thongboonkerd, 2024), (Sheng and Zhuang, 2020). Further mechanistic investigations are required to clarify the contribution of pEMT to renal fibrosis. Nevertheless, our findings support the possibility that pEMT may contribute to fibrosis within the specific pathophysiological context of Ang II and HFD co-administration.

Additionally, fibroblast proliferation, as assessed by the BrdU assay, was notably enhanced by the combined treatment, as opposed to each treatment administered separately. Interestingly, the use of 5 μg/mL oxLDL in our study showed a tendency to decrease proliferation, which was counteracted by the administration of an ARB but not a Gq inhibitor. These findings suggest that the presence of Ang II leads to a significant transformation in the function of oxLDL, primarily due to its altered influence within the AT1-LOX-1 complex. Taken together, these results suggest that the simultaneous binding of oxLDL to LOX-1 and Ang II to AT1 results in a Gq-biased shift in AT1 activation, leading to a cellular phenomenon that could potentially contribute to renal fibrosis.

In an animal study, we introduced a biological environment in which both circulating Ang II and oxLDL (an LOX-1 ligand) were increased in mice. Previous studies using mice fed an HFD have consistently reported the onset of renal injury, as determined by various measurements (Jiang et al., 2005; Kume et al., 2007; Yamamoto et al., 2017; Sun et al., 2020; Yu et al., 2022). In contrast, 6 wk of HFD feeding without Ang II treatment did not alter renal function in our mice. This can be attributed to the lack of obesity induced by the HFD in this study. We used this diet based on a previous study that confirmed increased circulating LOX-1 ligand levels without body weight gain in mice (Sato et al., 2008). In our experiments, this diet led to a decrease in body weight, likely due to reduced food intake in HFD-fed mice (Figure 7—figure supplement 1d, e). Although modest, this weight reduction may influence renal function. Obesity is a well-established and clinically proven risk factor of renal dysfunction. The mechanisms underlying this association are complex and involve various factors other than lipid abnormalities, such as hemodynamic changes that affect kidney circulation and the impact of adipose tissue on the production of adipokines and other inflammatory mediators (García-Carro et al., 2021; Tsuboi et al., 2017). Consequently, we observed the influence of elevated lipid particle levels on renal function, independent of obesity. We found that the effect of an HFD became obvious with an increase in the Ang II load in WT mice. In particular, in WT mice treated with high-dose Ang II, which elevated systolic BP by approximately 30 mm Hg, an HFD induced notable increases in urinary reactive oxygen species and urinary albumin. In contrast, an HFD had no impact on Ang II-infused LOX-1 KO mice, as evidenced by equivalent urinalysis measurements for renal injury between the diets. Correspondingly, simultaneous administration of an HFD and Ang II resulted in a consistent alteration in the expression of genes related to renal injury, including fibrosis, inflammation, and oxidative stress, except for some genes in WT mice, but not in LOX-1 KO mice. This strongly suggests that the combined effect of Ang II and HFD on renal function is LOX-1 dependent. Nevertheless, it should be noted that the effect of high-dose Ang II infusion on BP tended to be less pronounced in LOX-1 KO mice compared to WT mice, although there were no differences in BP elevation between the diets in each group of mice. This reduction in BP may contribute to the decreased renal injury observed in LOX-1 KO mice, independent of the AT1/LOX-1 interaction. These findings align with those of previous studies indicating that LOX-1 knockout mice show resistance to Ang II-induced elevation of BP (Hu et al., 2008; Hu et al., 2009; Li et al., 2021.) Specifically, when mice were infused with 2 γ Ang II (equivalent to 25 g mice) for a duration of 28 d, wild-type mice experienced a BP increase exceeding 180 mmHg, while LOX-1 knockout mice demonstrated a reduction of approximately 40 mmHg in this elevation (Hu et al., 2008). Furthermore, the same research group reported that Ang II infusion led to less severe renal injury in LOX-1KO mice compared to WT mice (Hu et al., 2009). Importantly, these findings were observed in mice fed with an ND, suggesting that the protective effect of LOX-1 loss-of-function against Ang II-induced elevated BP occurs through the LOX-1-AT1 complex, independent of the presence of oxLDL. Additionally, under subpressor doses of Ang II, where no significant differences in BP were observed, HFD-fed WT mice still exhibited increased renal injury compared to ND-fed mice, an effect that was reduced in LOX-1 KO mice. These findings suggest that the protective effects of loss-of-function of LOX-1 are partly independent of BP changes, underscoring the role of the AT1/LOX-1 interaction in renal injury with Ang II and HFD co-treatment. We recognize that our single time-point analysis (1.5 mo post-treatment) also may limit these observations, as the effects of AT1/LOX-1 interaction on renal injury could vary with treatment duration. Taken together, the effects of LOX-1 on AT1 signaling are complex, involving both ligand-dependent and -independent mechanisms, and further investigation is required for a comprehensive understanding of the LOX-1-AT1 interaction.

Regarding the effects of AT1 and LOX-1 interaction on the renin-angiotensin system (RAS) and blood pressure, oxLDL binding to LOX-1 enhances AT1 receptor-mediated Gq signaling, thereby promoting Ang II effects such as vasoconstriction, oxidative stress, and inflammation, all of which contribute to elevated blood pressure. However, in HFD-fed mice treated with a pressor dose of Ang II, plasma aldosterone levels showed an increasing tendency but remained statistically non-significant compared with ND-fed mice (ND: 102.8±11.6 pg/mL vs. HFD: 141.8±15.0 pg/mL, p=0.081), as shown in Figure 7—figure supplement 3, indicating a limited response in aldosterone production under these conditions. Additionally, BP did not significantly change (Figure 7—figure supplement 2f, g), potentially due to heterogeneous cellular responses across cell types, as indicated by the lack of reaction in vascular endothelial cells, vascular smooth muscle cells, and macrophages (Figure 3—figure supplement 1), and/or possibly due to aldosterone saturation from the high Ang II dose.

Finally, the current findings unequivocally demonstrated the molecular interactions between key molecules associated with dyslipidemia and hypertension in the kidneys. Moreover, this interaction can be effectively inhibited by ARBs, suggesting an additive effect in preventing the development of CKD, particularly in patients with hypertension and dyslipidemia. Interestingly, Ang II-dependent hypertensive animal models, including constriction of the renal artery and infusion of Ang II in rats and mice, have revealed a progressive increase in intrarenal Ang II levels, surpassing what can be accounted for by circulating Ang II levels alone (Navar et al., 2011). This is due to Ang II-dependent renal activation of the RAS, as indicated by increased urinary angiotensinogen (AGT) secretion (Navar et al., 2011; Navar, 2013). Importantly, the elevation of urinary AGT is also evident in patients with various pathologies, including hypertension and CKD, implying that renal Ang II levels increase even in individuals who do not exhibit elevated levels of circulating Ang II (Kobori et al., 2009; Navar, 2013; Mills et al., 2012). Taken together, the current finding of the synergistic effect of Ang II and oxLDL on AT1 activation in renal tissue is highly relevant for the development of kidney disease. RAS inhibitors, ARB, and ACE inhibitors are prioritized therapies to prevent the development of CKD with proteinuria in patients with hypertension (Kidney Disease: Improving Global Outcomes Blood Pressure Work, G. KDIGO, 2021). In addition to the well-established inhibitory effects of Ang II on the contraction of efferent arterioles (Yang et al., 2011), a novel renal protective action of RAS inhibitors has been proposed. Particularly in hypertension accompanied by dyslipidemia, RAS inhibitors may exhibit anti-inflammatory, antifibrotic, and antioxidant effects in the kidneys by inhibiting the Gq signaling pathway through the AT1-LOX-1 complex in renal tubular cells and fibroblasts. In terms of ARBs’ effectiveness in inhibiting AT1/LOX-1 receptor conformational changes, all ARBs generally block the downstream signaling from AT1-LOX-1 interaction by preventing Ang II binding to AT1. Our previous study also showed that ARBs, including olmesartan, telmisartan, valsartan, and losartan, could inhibit AT1 activation by oxLDL in the absence of Ang II (Yamamoto et al., 2015). However, certain ARBs—olmesartan, telmisartan, and valsartan—also act as inverse agonists, reducing baseline AT1 activity by preventing conformational changes even without Ang II (Yamamoto et al., 2015). This inverse agonist property may offer additional therapeutic benefits by reducing receptor activation beyond what is achieved by simple antagonism in pathological states where AT1 activation occurs independently of Ang II, such as in oxLDL presence. Collectively, the current findings suggest that RAS inhibitors, some of which possess inverse agonist properties, can concomitantly mitigate the effect of increased renal Ang II and oxLDL levels on the development of CKD in patients with hypertension and dyslipidemia, although direct evidence in clinical studies to support this remains to be elucidated.

This study has several limitations as follows: (1) The kidney, a complex organ vital for maintaining homeostasis, comprises a myriad of distinct cell types working in concert to execute its multifaceted functions (Balzer et al., 2022). The experiments conducted in mice raised questions regarding the specific cell types implicated in the synergistic effect of Ang II and oxLDL within the LOX-1-AT1 complex in the kidney. Addressing this issue would ideally require single-cell analysis, which is a challenge for future research. (2) The study employed systemic LOX-1 knockout mice. For a more detailed analysis, a phenotypic investigation using renal tissue-specific LOX-1 and AT1 knockout mice is required. Of particular importance is the analysis using tubule-specific knockout mice, in which the localization of these components has been verified through immunohistochemical staining. (3) The administration of Ang II (both pressor and subpressor doses) and its combination with HFD did not result in any histological changes in terms of fibrosis and mesangial expansion, despite the observed alterations in the associated gene expression and urinalysis for renal injury. Alterations in gene expression and urinalysis for renal injury may be sensitive and relatively early phenomena, and this discrepancy could potentially be attributed to the relatively short intervention duration of 4 wk for combined HFD and Ang II administration. Therefore, concurrent pathohistological alterations in the renal tissue might become evident with a more extended intervention period. (4) This study was limited by its inability to detect the amplification of Gq signaling in mouse renal tissue due to the concurrent administration of Ang II and HFD. Overcoming this limitation is a challenge for future studies.

In conclusion, the current findings suggest that the simultaneous binding of oxLDL and Ang II to their respective receptors within the complex induces a distinct conformational change compared with the effect of each ligand alone. This unique conformational change results in the heightened activation of G protein signaling and subsequent unfavorable cellular reactions in renal component cells. The relevance of this phenomenon was confirmed in mouse models, in which renal dysfunction was prominently exacerbated when there was a concomitant increase in Ang II and oxLDL levels. Notably, this effect was abolished by the deletion of LOX-1, indicating LOX-1 dependency of this in vivo phenomenon (Figure 10). These findings indicate the clinical relevance of the direct interaction between hypertension and dyslipidemia and further support the clinical significance of RA inhibition in treating patients with CKD.

Figure 10

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All data supporting the findings of this study are available within the paper and its supplementary information; source data are provided in this paper.

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Author details

1. Jittoku Ihara

   Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Yibin Huang

   Competing interests

   No competing interests declared

2. Yibin Huang

   1. Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
   2. Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – original draft

   Contributed equally with

   Jittoku Ihara

   Competing interests

   No competing interests declared

3. Yoichi Takami

   Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

   Contribution

   Conceptualization, Data curation, Supervision, Funding acquisition, Validation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   takami@geriat.med.osaka-u.ac.jp

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9018-6707

4. Yoichi Nozato

   Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   yoichi.nozato@geriat.med.osaka-u.ac.jp

   Competing interests

   No competing interests declared

5. Toshimasa Takahashi

   1. Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
   2. Department of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   tkhstsms@hotmail.co.jp

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5203-155X

6. Akemi Kakino

   Department of Molecular Pathophysiology, Shinshu University Graduate School of Medicine, Matsumoto, Japan

   Contribution

   Resources, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

7. Cheng Wang

   Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

8. Ziwei Wang

   Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. Yu Guo

   Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

10. Weidong Liu

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

11. Nanxiang Yin

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

12. Ryoichi Ohara

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

13. Taku Fujimoto

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

14. Shino Yoshida

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

15. Kazuhiro Hongyo

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

16. Hiroshi Koriyama

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

17. Hiroshi Akasaka

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

18. Hikari Takeshita

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Formal analysis

    Competing interests

    No competing interests declared

19. Shinsuke Sakai

    Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Supervision, Investigation

    Competing interests

    No competing interests declared

20. Kazunori Inoue

    Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Supervision, Writing – review and editing

    Competing interests

    No competing interests declared

21. Yoshitaka Isaka

    Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Supervision

    Competing interests

    No competing interests declared

22. Hiromi Rakugi

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Conceptualization, Supervision, Funding acquisition, Writing – original draft

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6508-4338

23. Tatsuya Sawamura

    Department of Molecular Pathophysiology, Shinshu University Graduate School of Medicine, Matsumoto, Japan

    Contribution

    Conceptualization, Resources, Supervision, Writing – original draft, Writing – review and editing

    Competing interests

    No competing interests declared

24. Koichi Yamamoto

    Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Writing – original draft, Project administration, Writing – review and editing

    Competing interests

    No competing interests declared

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