Angiotensin 1-7 reduces lipid deposition in the renal tubules of high-fat fed mice

doi:10.21203/rs.3.rs-3875847/v1

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Angiotensin 1-7 reduces lipid deposition in the renal tubules of high-fat fed mice

https://doi.org/10.21203/rs.3.rs-3875847/v1

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Background

To investigate the effects of angiotensin 1–7 (Ang-(1–7)) on proximal tubules in mice fed a high-fat diet (HFD).

Methods

Mice were randomly divided into three groups, including the control group (mice fed a standard rodent chow diet), HFD group, and HFD group treated with Ang-(1–7). At the end of the experiment, 24-h urine samples and kidney specimens were collected. We evaluated proximal tubule injury with PAS. Renal Oil Red O staining and immunofluorescence staining were used to disclose the expression of lipid deposition. Endoplasmic reticulum stress, inflammation and apoptosis were tested by Western blotting.

Results

Serum creatinine, blood urea nitrogen, and urinary albumin were elevated in HFD mice, while urinary albumin was decreased after Ang-(1–7) treatment. Ang-(1–7) dramatically inhibited the development of vacuolated tubular cells and lipid deposition while decreasing the expression of perilipin-2 and CD36. Ang-(1–7) also ameliorated the increase in endoplasmic reticulum stress and apoptosis. Furthermore, increased TNF-α, MCP-1, and IL-1β levels in HFD mice were inhibited by Ang-(1–7) treatment.

Conclusions

Ang-(1–7) treatment mediated reno-protection by attenuating lipotoxicity to inhibit inflammation and endoplasmic reticulum stress-induced apoptosis in HFD mice. These findings may offer a novel therapy for HFD-related renal injury.

Angiotensin 1–7

lipotoxicity

endoplasmic reticulum stress

inflammation

apoptosis

Excess lipid content characterized by ectopic lipids has been identified as a pathologic factor in chronic kidney disease (CKD) (1). Inhibition of lipotoxicity promoting tubular atrophy and tubular epithelial cell death prevented the progression of renal injury (2). In obese patients, the excess fatty acid load contributed to tubulointerstitial damage in tubular cells (3). Obesity can induce endoplasmic reticulum (ER) stress in rodents and humans. ER stress has been associated with a high-fat diet (HFD)-induced obesity, insulin resistance, and obesity-related glomerulopathy (4, 5). Increased saturated fatty acids induce proximal tubule cell apoptosis and renal injury in response to ER stress (5, 6).

Inflammation is correlated with the pathogenesis of nephropathy. Obesity is considered to be an inflammatory condition associated with increased proinflammatory cytokines and chemokines (7). Obese patients with nephropathy were linked with high levels of inflammatory cytokines (8). The activation of the renin angiotensin system (RAS) plays a critical role in the progression of HFD-induced kidney diseases. The intrarenal RAS was significantly stimulated in spontaneously hypertensive rats fed an HFD, inducing fatty kidneys and renal inflammation (9). Ang-(1–7) is a bioactive heptapeptide generated from angiotensin II (Ang II) through angiotensin-converting enzyme 2 (ACE2). Ang-(1–7) mainly combines with the endogenous receptor Mas to reduce Ang II expression, leading to inhibition of inflammation and reduction of ER stress (10–12). Ang-(1–7) significantly reduced fibrosis, inflammation, and lipotoxicity in the kidneys of db/db mice (13). Our study tried to assess the effects of Ang-(1–7) on proximal tubules in HFD mice.

Materials Ang-(1–7) and palmitate (PA) were purchased from Med Chem Express (Monmouth Junction, NJ, USA). Anti-CHOP (#2895), anti-BIP (#3177T), anti-p-eIF2α/eIF2α (#3597) and anti-cleaved caspase 3 (#9661) were purchased from Cell Signaling Technology (Beverly, MA, USA). Anti-Mas (ab156018), anti-perilipin-2 (PLIN2) (ab108323), anti-CD36 (ab133625), anti-MCP-1 (ab7202), anti-IL-1β (ab2105), anti-Bcl-2 (ab182858), anti-Bax (ab32503), anti-LAMP2 (ab25631), anti-p62 (ab109012) and anti-β-actin (ab8226) were obtained from Abcam (Cambridge, MA, USA). The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) kit was obtained from Roche (Takara Bio Inc., Tokyo, Japan). The Triglyceride Colorimetric Assay Kit, Urea Fluorometric Assay Kit, creatinine enzyme-linked immunosorbent assay (ELISA) Kit, and TNF-α ELISA Kit were purchased from Cayman (Biomol GmbH, Germany). Cholesterol ELISA kits, free fatty acid ELISA kits, and urinary albumin ELISA kits were obtained from Yaji (Shanghai, China).

Animal Models All animal experiments were performed with the approval of the Animal Care Committee at Fudan University (Shanghai, China). Twenty six-week-old male C57BL/6J mice were randomly divided into two groups: mice fed a standard rodent chow (10% of total calories from fat) diet (marked as CON, n = 6) and a high fat (60% of total calories from fat) diet (n = 14) for 12 weeks. The HFD mice were then divided into two groups receiving either Ang-(1–7) (100 ng·kg^− 1 ·min^− 1, designated HFDA, n = 7) or saline (designated HFD, n = 7) by micro-osmotic pumps for 4 weeks. At the 16th week, 24-h urine samples were collected from the mice using metabolic cages. At the end of the experiment, the mice were anesthetized with phenobarbital sodium at a working concentration of 1% and a dose of 50mg/kg. The experimental mice were sacrificed for cervical dislocation under anesthesia. Blood and kidney specimens were obtained. After centrifugation (3,500 rpm for 15 min), the serum was collected and stored at − 80°C until further use. The kidney specimens were frozen in liquid nitrogen and stored at − 80°C. The study is reported in accordance with ARRIVE guidelines

Cell culture

HK2 cells were cultured in DMEM/F12 containing 5% FBS at 37°C. PA medium was dissolved by mixing PA at a concentration of 0.4 mM with 37.88 µM BSA. HK2 cells cultured with BSA were used as the control. Cells were starved overnight in culture medium without FBS prior to intervention with PA or Ang-(1–7) (100 nM) for 24 h and lysed with RIPA buffer for western blot analysis. HK2 cells were cultured on 24-well plates and fixed with 4% paraformaldehyde for immunofluorescence.

Renal Oil Red O Staining Kidney tissue was fixed in 4% paraformaldehyde, embedded in paraffin and cut into 10-µm sections. Sections were rinsed three times in PBS for 5 min, infiltrated with 60% isopropylene for 1 ~ 2 min and then permeabilized with 60% Oil Red O solution for 2 ~ 5 min. The staining solution was removed by rinsing in 60% isopropylene, and the nuclei were counterstained with hematoxylin for 1 min.

Immunohistochemistry Kidney tissue sections were dewaxed and rehydrated. After blocking endogenous peroxidase, antigen retrieval was performed in citrate buffer by microwave treatment. Sections were blocked with 5% fetal bovine serum at room temperature for 1 h, and then the primary antibodies were added and incubated overnight at 4°C. On the following day, the slides were exposed to secondary antibodies at room temperature for 1 h. Finally, ABC complexes were added to the slides and incubated at 37°C for 30 min, and peroxidase activity was measured with DAB.

Immunofluorescence Staining Kidney tissue sections were dewaxed and rehydrated. Antigens were retrieved in citrate buffer, and the sections were blocked with 5% fetal bovine serum. Primary antibodies were then added, and the sections were incubated at 4°C overnight. Slides were exposed to fluorescent antibodies for 1 h at room temperature. After washing in PBS, the slides were mounted with DAPI.

Western Blot Renal tissues were centrifuged, and the supernatant was collected. The protein concentration was determined with a BCA protein assay kit (Beyotime Biotechnology, Shanghai, China), and equal amounts of proteins were loaded onto gels. After separation and transfer, the proteins were transferred to a PVDF membrane. After blocking with 5% milk on a shaker for 1 h, the membrane was incubated with primary antibodies at 4°C overnight, followed by incubation with secondary antibodies (anti-rabbit or anti-mouse horseradish peroxidase-conjugated antibodies purchased from Beyotime Biotechnology, Shanghai, China) for 1 h at room temperature.

ELISA Serum creatinine, blood urea nitrogen (BUN), urinary albumin, and cytokines (TNF-α) were measured by ELISA kits. The antibody dilution was added to the plate at 4°C overnight. After washing the wells with PBST, the samples were diluted, added to the plate and incubated on a shaker for 2 h. The secondary antibody was then added, followed by the HRP reaction. Finally, the colorimetric solution was added, and OD values were measured by an ELISA plate reader.

Statistical analysis Results are presented as the means ± standard deviations. Data were analyzed by one-way ANOVA. Statistical significance was assumed at p < 0.05.

Levels of lipid metabolism index, kidney function, and Mas Expression Lipid metabolism index, including total cholesterol, triglyceride, and free fatty acid, was measured by ELISA. The fat mice treated with Ang-(1–7) markedly decreased the high level of the lipid metabolism index compared with the HFD group (Fig. 1A-1C). Serum creatinine and BUN were elevated in HFD mice, and Ang-(1–7) treatment showed no significant changes in serum creatinine (Fig. 1D). Urinary albumin was increased in the HFD group and significantly decreased with Ang-(1–7) treatment (Fig. 1F). Ang-(1–7) interacting with the Mas receptor exerts the opposite effect on Ang II. Immunohistochemistry and Western blotting illustrated that the expression of Mas was significantly increased in HFD mice compared with the CON group, while Mas expression was restored after Ang-(1–7) treatment (Fig. 2A-2D)..

Proximal tubule injury and lipotoxicity Periodic acid-Schiff (PAS) staining demonstrated that tubular cells were vacuolated in high-fat diet mice, and Ang-(1–7) dramatically inhibited the development of vacuolated tubular cells (Fig. 3A). Oil Red O Staining indicated that lipid deposition in the renal tubules induced by the HFD was ameliorated by Ang-(1–7) (Fig. 3B). PLIN2 and CD36 promote the uptake of fatty acids into cells, which contributes to lipid metabolism. Increased fatty acid transport was associated with PLIN2 and CD36 expression, resulting in heterotopic lipids. Compared to CON mice, HFD mice displayed markedly increased PLIN2 and CD36 expression, as shown by immunofluorescence and western blotting. The expression of PLIN2 and CD36 was reduced by Ang-(1–7) treatment (Fig. 3C-3H).

ER Stress and Apoptosis pathway Western blotting showed a significant increase in ER stress markers, including BIP, p-eIF2α and CHOP proteins, in HFD mice, while Ang-(1–7) decreased the expression of these proteins (Fig. 4A and B). Bcl-2, an anti-apoptosis protein, was reduced in the HFD group, and Ang-(1–7) treatment improved its expression. Bax and cleaved caspase3 were increased in HFD mice, and Ang-(1–7) treatment ameliorated all changes (Fig. 5A and B). The percentage of cells containing TUNEL-positive nuclei was significantly increased in HFD mice, which was markedly reduced by Ang-(1–7) (Fig. 5C and D).

Inflammatory FFAs stimulate adipose tissue to release excess inflammatory factors such as TNF-α, IL-1β, and MCP-1. ELISA indicated that the HFD significantly increased TNF-α levels, which were attenuated after Ang-(1–7) treatment (Fig. 6A). Western blot analysis also showed that MCP-1 and IL-1β protein were remarkably activated compared to the CON mice but inhibited with Ang-(1–7) treatment (Fig. 6B and C).

Ang-(1–7) treatment promotes lipid metabolism in vitro. We assessed lipid droplet deposition in PA-cultured HK2 cells by Oil Red O Staining. Ang-(1–7) treatment decreased Oil Red O deposition in PA-cultured HK2 cells. Expression of lipoprotein PLIN2 was markedly reduced with Ang-(1–7) treatment compared to PA-cultured HK2 cells. P62 expression was increased after exposure to the PA culture solution, while was also markedly inhibited in the presence of Ang-(1–7) in vitro. These findings demonstrated that Ang-(1–7) intervention promoted lipid metabolism in vitro (Fig. 7A-7D).

Obesity is associated with CKD in mice and humans with accumulating evidence. Ang-(1–7) was proven to improve the metabolic profile in diet-induced obesity through two components: activation of hormone-sensitive lipase and deactivation of perilipin, leading to the amelioration of Akt phosphorylation (14). We demonstrated that Ang-(1–7) reduced metabolic disorder and dyslipidemia and decreased urinary albumin in HFD mice. Ang-(1–7) reversed renal lipotoxicity in HFD mice by reducing lipid deposition and decreasing the expression of CD36 and PLIN2 in proximal tubules. In addition, the reno-protective effects of Ang-(1–7) appeared to reduce apoptosis induced by the HFD via amelioration of ER stress.

A novel branch of the RAS, comprised of ACE2, Ang-(1–7) and Mas, counteracts the deleterious actions mediated by the classical ACE/Ang II/AT1 axis (11, 15). Increased adiponectin levels and decreased NADPH oxidase mRNA expression against oxidative stress in adipocytes treated with Ang-(1–7) were attributed to the inhibition of RAS activation (16). RAS was activated in rats fed a HFD due to increased Ang II release (9). Angiotensin receptor blocker treatment plays a renoprotective role by suppressing Ang II-mediated AT1 receptor signaling and restoring renal Mas levels in streptozotocin-treated diabetic mice (17). In our study, the increased expression of Mas induced by the HFD was significantly reduced by Ang-(1–7) treatment. Ang-(1–7) antagonized RAS axis activation to protect against proximal tubule injury induced by HFD feeding through a Mas receptor-dependent pathway. The mechanism accounting for the increase in Mas receptor expression in the HFD mice was unclear. We found that increased Mas expression was concentrated in the renal tubule with vacuolar degeneration by PAS. Mas expression was increased in the adipose tissue of metabolic syndrome rats, suggesting that a high-fat diet was responsible for increased Mas expression (18). Vijayakumar S et al. reported that Ang-(1–7) activated Mas expression in db/db mice (19), while in line with our study, the number of Mas receptors was decreased in diabetic renal tissue with Ang-(1–7) injection compared to diabetic rats (20). Ang-(1–7) treatment reduced the levels of Ang II to antagonize RAS activation, inhibiting renal apoptosis and fibrosis in obstructive nephropathy (21). Ang-(1–7) was proven to attenuate hypertension, while Martina W et al. indicated that Ang-(1–7) treatment could not attenuate obesity-induced hypertension (22).

Mice fed with HFD showed a significant increase in lipid accumulation in glomerular and tubulointerstitial cells, contributing to glomerulosclerosis and proteinuria. Ectopic lipids are a central factor in the progression of renal injury. We found that treatment with GLP-1 attenuated lipid accumulation in renal tissue and reduced HFD-induced kidney injury (5). Ang-(1–7) treatment reduced renal triacylglycerol levels in db/db kidneys via normalization of SIRT1 and PPARα levels (13). We showed here that lipid deposition in the renal tubules was ameliorated by Ang-(1–7). The process of lipid influx into macrophages and mesangial cells is mediated by proteins including CD36. Inhibition of CD36 expression can ameliorate the progression of CKD and attenuate tubulointerstitial fibrosis and inflammation (1, 23). PLIN2 is expressed in nonadipose tissues to regulate the storage and hydrolysis of lipids. The absence of PLIN2 prevented HFD-induced obesity and hepatic lipid accumulation in mice (24), demonstrating that inhibition of PLIN2 expression ameliorated HFD-induced lipid toxicity. Similarly, in the present study, Ang-(1–7) treatment ameliorated lipid deposition and lipotoxicity in HFD mice and PA-cultured HK2 cells by reducing the expression of PLIN2.

ER stress is involved in various kidney diseases, including proteinuric diseases, ischemic injury, tubular disease and nephrotic syndrome (25). The expression of BIP and CHOP and apoptosis were increased in streptozotocin-induced ER stress in diabetic rats (26). Lindenmeyer et al. found that levels of unfolded protein were elevated in renal tubular cells of patients with diabetic nephropathy, thereby promoting CHOP-mediated apoptosis (27). Accumulating evidence has shown that ER stress is activated along with the increased expression of fatty acids (6, 28). In C57BL/6J male mice, HFD increased ER stress and apoptosis by increasing the expression of CHOP and phosphorylation of PERK (29). Inhibition of the ER stress response may be protective for patients with ER stress-related renal diseases. Our previous study illustrated that GLP-1 treatment exerted reno-protective effects against saturated fatty acid-induced ER stress and apoptosis of renal tubular cells in HFD mice via inhibition of AT1R expression, both in vitro and in vivo (5). Acetaminophen attenuated ER stress-induced apoptosis to protect against renal injury by reducing the eIF2α-ATF4-CHOP signaling pathway and renal JNK phosphorylation in the obese Zucker rat model (30). Stearoyl-CoA desaturase-1, an FFA metabolism-related enzyme, reduced saturated fatty acid-induced apoptosis by reducing ER stress in renal proximal tubular epithelial cells (31). We found a significant increase in ER stress markers (eIF2α, BIP, and CHOP) in the HFD group compared with the controls, which were diminished with Ang-(1–7) treatment. Furthermore, the anti-apoptosis protein Bcl-2 was reduced in the HFD group and was restored by Ang-(1–7). Ang-(1–7) treatment also attenuated the increase in apoptotic proteins induced by the HFD, partly by inhibiting the activation of ER stress and the eIF2α-ATF4-CHOP signaling pathway.

HFD-induced renal injury is associated with upregulated cytokine levels and inflammatory pathways. Inhibition of inflammation delays the progression of kidney disease, including renal interstitial disease and diabetic nephropathy. The RAS is associated with the pathogenesis of inflammatory responses. Recent studies have shown that the Ang-(1–7)/Mas axis may play a relevant role in inflammation. Ang-(1–7) negatively modulates the recruitment of inflammatory cells, activation of nuclear transcription factors and cytokine release (32). The anti-inflammatory effect of Ang-(1–7) alleviated kidney damage caused by HFD via the LDLr-SREBP2-SCAP pathway (33). In our research, the HFD-induced increase in inflammatory cytokine levels was attenuated by Ang-(1–7) treatment.

Ang-(1–7) administration was demonstrated to decrease serum creatinine levels (34). However, Singh T et al. indicated that serum creatinine and creatinine clearance remained unaffected by Ang-(1–7) treatment (35). Shao Y et al. even reported that serum creatinine was worse in diabetic rats after treatment with constant Ang-(1–7) vein injection for 6 weeks (20). The effect of Ang-(1–7) on serum creatinine is controversial. We found that Ang-(1–7) treatment did not decrease serum creatinine in the HFD group, although lipid metabolism and urinary albumin were ameliorated. The mechanism remains to be further researched.

Obese individuals had decreased Ang (1–7) peptide levels (36). Oral treatment with Ang-(1–7) in high-fat feed rats improved metabolism and downregulated the expression of inflammatory proteins, including TLR4 and NF-κB (37). Ang-(1–7) intervention could reduce the adiposity index of transgenic rats, accompanied by a decrease in lipogenesis (38). The data show that Ang-(1–7) treatment mediated reno-protection in HFD mice by attenuating lipotoxicity to inhibit ER stress-induced apoptosis and inflammation. These findings may offer novel therapeutic approaches for HFD-related proximal tubule injury.

Ethics approval and consent to participate

All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee at Fudan University (Shanghai, China, FDUN-2011070435).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests

The authors declare that there are no conflicts of interest.

Funding

This work was supported by grants from the Natural Science Foundation of Jiangsu, China (BK20181085).

Authors’ contributions

All authors in this study have contributed to this manuscript and approve of this submission. Zheng qin and Huanhuan Zhu designed and drafted the manuscript. Hongqing Cui performed the experiment. Zheng qin analyzed the data. Honglei Guo contributed to the design and provided critical revisions to this manuscript.

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No competing interests reported.

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Angiotensin 1-7 reduces lipid deposition in the renal tubules of high-fat fed mice

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