GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity

Jian Lu, Pei Pei Chen, Jia Xiu Zhang, Xue Qi Li, Gui Hua Wang, Ben Yin Yuan, Si Jia Huang, Xiao Qi Liu, Ting Ting Jiang, Meng Ying Wang, Wen Tao Liu, Xiong Zhong Ruan, Bi Cheng Liu, Kun Ling Ma, Jian Lu, Pei Pei Chen, Jia Xiu Zhang, Xue Qi Li, Gui Hua Wang, Ben Yin Yuan, Si Jia Huang, Xiao Qi Liu, Ting Ting Jiang, Meng Ying Wang, Wen Tao Liu, Xiong Zhong Ruan, Bi Cheng Liu, Kun Ling Ma

Abstract

Rationale: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. Methods: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. Results: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. Conclusion: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity.

Keywords: AMPKα activity; GPR43; diabetic nephropathy; gut microbiota dysbiosis; podocyte insulin resistance.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

© The author(s).

Figures

Figure 1
Figure 1
Diabetes mellitus enhances the expression of GPR43 in the kidney. (A) Representative confocal immunofluorescent images illustrating an increase in the expression of GPR43 in the kidneys of the patients with DN of various degrees of renal biopsy-proved pathological damage. Scale bar, 50 µm. (B) Western blotting analysis of expression of GPR43 protein in the renal cortex of vehicle- or streptozotocin (STZ)-treated diabetic mice at Week 12 (mean ± SD, *P < 0.05 vs. Ctrl, n = 3). (C) Representative confocal immunofluorescent images illustrating the expression of phosphorylated Akt and WT-1 in the kidney of healthy controls and the patients with DN of various degrees of renal biopsy-proved pathological damage. Scale bar, 50 µm.
Figure 2
Figure 2
The effects of acetate-induced GPR43 activation on podocyte injury. (A) Real-time PCR analysis of the mRNA levels of GPR43, GPR41, and Oflr78 in podocytes, which were treated with different concentrations of acetate (3, 5, 10, 20 and 40 mmol/L) under the high glucose condition (30 mmol/L D-glucose, HG) for 24h (mean ± SD, *P < 0.05, **P < 0.01 vs. Ctrl, n = 3). (B) Western blotting analysis of the protein levels of GPR43 in podocytes, which were treated with different concentrations of acetate (3, 5, 10, 20 and 40 mmol/L) under the HG condition for 24h (mean ± SD, *P < 0.05 vs. Ctrl, n = 3). (C) Real-time PCR analysis of the mRNA levels of nephrin, collagen I and α-SMA in podocytes, which were treated with different concentrations of acetate (3, 5, 10, 20 and 40 mmol/L) under the HG condition for 24h (mean ± SD, *P < 0.05 vs. Ctrl, n = 3). (D) Western blotting analysis of the protein levels of nephrin, collagen I and α-SMA in podocytes, which were treated with different concentrations of acetate (3, 5, 10, 20 and 40 mmol/L) under the HG condition for 24h (mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001 vs. Ctrl, n = 3). (E) Western blotting analysis of the protein level of nephrin, collagen I and α-SMA in podocytes (mean ± SD, *P < 0.05 vs. HG+ siRNA control, #P < 0.05 vs. HG + acetate + siRNA control, n = 3).
Figure 3
Figure 3
The activation of GPR43 suppressed insulin signalling in podocytes. (A) Inhibitory effects of acetate (3, 5, 10, 20 and 40 mmol/L) on Akt phosphorylation in podocytes under the HG condition for 24h. (mean ± SD, *P < 0.05, **P < 0.01 vs. Ctrl, n = 3). (B) Inhibitory effects of acetate (10 mmol/L) on Akt phosphorylation in podocytes (mean ± SD, *P < 0.05 vs. Ctrl, ***P < 0.001 vs. Ctrl, and ###P < 0.001 vs. HG, n = 3). (C) Inhibitory effects of acetate (10 mmol/L) on the suppression of insulin-induced Akt phosphorylation in podocytes (mean ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. Insulin, n = 3). (D) Inhibitory effects of acetate (3, 5, 10, 20 and 40 mmol/L) on the suppression of the IRβ and IRS1 mRNA expression in podocytes under the HG condition for 24h (mean ± SD,*P < 0.05 vs. Ctrl, n = 3). IRβ, insulin receptor β; IRS1, insulin receptor substrate 1. (E) Inhibitory effects of acetate (3, 5, 10, 20 and 40 mmol/L) on the suppression of IRβ and IRS1 protein expression in podocytes under the HG condition for 24h (mean ± SD,*P < 0.05, **P < 0.01, ***P < 0.001 vs. Ctrl, n = 3). (F) Podocytes significantly increased 2-NBDG uptake in response to insulin, and acetate (10 mmol/L) selectively reduced 2-NBDG uptake (mean ± SD, *P < 0.05 vs. Ctrl, ##P < 0.01 vs. Insulin, n = 3). (G) Representative confocal immunofluorescent images illustrating the suppression of the insulin-induced translocation of GLUT4 protein to the cellular membrane of podocytes mediated by acetate (GLUT4, Green; DAPI, Blue; original magnification × 600, scale bars, 50 µm). (H) Effects of GPR43 knockdown by siRNA on restoration of insulin-induced Akt phosphorylation regulated by acetate (mean ± SD, *P < 0.05 vs. HG + siRNA control, #P < 0.05 vs. HG + acetate + siRNA control, n = 3). (I) Effects of GPR43 inhibition by GLPG0974 on restoration of insulin-induced Akt phosphorylation regulated by acetate (mean ± SD, **P < 0.01 vs. HG + siRNA control, ##P < 0.01 vs. HG + acetate + siRNA control, n = 3).
Figure 4
Figure 4
GPR43 deletion attenuated podocyte injury and albuminuria of diabetic mice. (A) Real-time PCR of the GPR43 mRNA expression in the pooled renal cortex samples from Ctrl and GPR43 KO mice (means ± SD, ****P < 0.0001 vs. Ctrl, n = 6). (B) Representative Western blotting images and densitometric analysis of the GPR43 protein expression in the renal cortex in the four groups of mice (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (C) Representative confocal microscopic images illustrating the expression of GPR43 and WT-1 in podocytes from the four groups of mice (original magnification × 400, scale bars, 50 µm). (D) The levels of random blood glucose of the four groups of mice were taken every two weeks during the study. (E) Kidney weight to body weight ratio was elevated in the DM mice compared with that in the Ctrl mice and significantly reduced in the GPR43 KO+DM mice (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (F) Urinary albumin-to-creatinine ratio (ACR) was detected in spot urine samples of mice collected respectively at Week 4, 8 and 12. ACR was elevated in the DM mice compared to that in the Ctrl mice; however, ACR was significantly reduced in the GPR43 KO+DM mice at Weeks 8 and 12 after the induction of diabetes (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (G) Lack of differences in the serum levels of BUN and Scr in four groups of mice. BUN, blood urea nitrogen. Scr, serum creatinine. (H) Representative images of PAS-stained kidney sections of all groups of mice (original magnification ×400, scale bars, 50 µm). Bar graph analysis of the semi-quantification estimate of the mesangial expansion score (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (I) Representative Western blotting images and densitometric analysis of collagen I and fibronectin in the renal cortex samples of all groups of mice (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (J) Representative images and estimation of ultrastructural changes in podocyte morphology, including podocyte effacement and glomerular basement membrane (GBM) thickness, observed by electron microscopy (original magnification × 40,000, scale bars, 500 nm). (K) Representative confocal immunofluorescent images of WT-1 staining in the kidney sections of all groups of mice (original magnification × 400, scale bars, 50 µm). The WT-1-positive nuclei were statistically counted (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (L) Representative confocal microscopic images showing the expression of pAkt in podocytes from various groups of mice (original magnification × 400, scale bars, 50 µm). (M) Representative Western blotting images of the pAkt and total Akt protein expression in the renal cortex samples of the four groups of mice (means ± SD, **P < 0.01 vs. Ctrl, #P < 0.05 vs. DM). (N) Principal component analysis (PCA) of distances between the communities of the faecal microbiota in the four groups of mice.
Figure 5
Figure 5
The treatment with broad-spectrum antibiotics or faecal microbiota transplantation (FMT) improved glomerular injury in STZ-induced diabetic rats. (A) Serum level of glucose was elevated in DM rats compared to that in Ctrl rats significantly reduced in DM+AB rats (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (B) Serum level of acetate was elevated in DM rats compared to that in the Ctrl rats and significantly reduced after the treatment with antibiotics or FMT (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (C) Representative Western blotting images showing that the treatment with antibiotics or FMT reduced the expression of GPR43 in the kidney of DM rats (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (D) Representative confocal microscopic images showing the expression of GPR43 in podocytes from various groups of rats (original magnification × 400, scale bars, 50 µm). (E) Urinary albumin to creatinine ratio (ACR) was elevated in DM rats compared with that in the Ctrl rats and significantly reduced after the treatment with antibiotics or FMT (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (F) Representative images of the PAS-stained kidney sections of all groups of rats (original magnification × 400, scale bars, 50 µm). Bar graphs showing semi-quantitative estimation of the mesangial expansion score (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (G) Representative photomicrographs of the glomerular basement membrane (GBM) thickness and the degree of foot processes in various groups of rats assayed by transmission electron microscopy (TEM) analysis (original magnification ×40,000, scale bars, 500 nm). (H) Representative confocal immunofluorescent images of WT-1 staining in the kidney sections in all groups of rats (original magnification ×400, scale bars, 50 µm). The WT-1-positive nuclei were statistically counted (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (I) Representative confocal microscopic images showing the expression of pAkt in podocytes from various groups of rats (original magnification ×400, scale bars, 50 µm). (J) Representative Western blotting images and densitometric analysis of pAkt and total Akt proteins in the renal cortex samples of all groups of rats (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM).
Figure 5
Figure 5
The treatment with broad-spectrum antibiotics or faecal microbiota transplantation (FMT) improved glomerular injury in STZ-induced diabetic rats. (A) Serum level of glucose was elevated in DM rats compared to that in Ctrl rats significantly reduced in DM+AB rats (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (B) Serum level of acetate was elevated in DM rats compared to that in the Ctrl rats and significantly reduced after the treatment with antibiotics or FMT (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (C) Representative Western blotting images showing that the treatment with antibiotics or FMT reduced the expression of GPR43 in the kidney of DM rats (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (D) Representative confocal microscopic images showing the expression of GPR43 in podocytes from various groups of rats (original magnification × 400, scale bars, 50 µm). (E) Urinary albumin to creatinine ratio (ACR) was elevated in DM rats compared with that in the Ctrl rats and significantly reduced after the treatment with antibiotics or FMT (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (F) Representative images of the PAS-stained kidney sections of all groups of rats (original magnification × 400, scale bars, 50 µm). Bar graphs showing semi-quantitative estimation of the mesangial expansion score (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (G) Representative photomicrographs of the glomerular basement membrane (GBM) thickness and the degree of foot processes in various groups of rats assayed by transmission electron microscopy (TEM) analysis (original magnification ×40,000, scale bars, 500 nm). (H) Representative confocal immunofluorescent images of WT-1 staining in the kidney sections in all groups of rats (original magnification ×400, scale bars, 50 µm). The WT-1-positive nuclei were statistically counted (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (I) Representative confocal microscopic images showing the expression of pAkt in podocytes from various groups of rats (original magnification ×400, scale bars, 50 µm). (J) Representative Western blotting images and densitometric analysis of pAkt and total Akt proteins in the renal cortex samples of all groups of rats (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM).
Figure 6
Figure 6
The activation of GPR43 suppressed insulin signalling via downregulation of AMPKα activity. (A) Inhibitory effects of acetate on AMPKα phosphorylation in podocytes which were treated with different concentrations of acetate (3, 5, 10, 20 and 40 mmol/L) under the HG condition for 24h (means ± SD, *P < 0.05, **P < 0.01 vs. Ctrl, n = 3). (B) Podocytes were transfected with GPR43 siRNA for 12h and then stimulated with HG or HG plus acetate for 24h. The rescue effects of the GPR43 knockdown on AMPKα phosphorylation which was inhibited by acetate (means ± SD, *P < 0.05 vs. HG+ siRNA control, ##P < 0.01 vs. HG+acetate+ siRNA control, n = 3). (C) Podocytes were pretreated with a GPR43 inhibitor (GLPG0974, 10 µmol/L) for 12h and then stimulated with HG or HG plus acetate for 24h. The rescue effects of GPR43 inhibition on AMPKα phosphorylation which was inhibited by acetate (means ± SD, *P < 0.05 vs. Insulin, #P < 0.05 vs. Insulin + acetate, n = 3). (D) Western blotting analysis of AMPKα phosphorylation in renal tissue samples from the four groups of mice (Ctrl, GPR43 KO, DM and GPR43 KO+DM) (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (E) Effects of the activation AMPKα signalling mediated by AICAR (10 µmol/L) on restoration of insulin-induced Akt phosphorylation inhibited by acetate (means ± SD, *P < 0.05 vs. insulin, n = 3). (F) The effects of GPR43 knockdown on PKC and PLCγ1 phosphorylation in podocytes which was induced by acetate (mean ± SD, *P<0.05, ***P<0.001 vs. HG + siRNA control, ##P < 0.01, ###P < 0.001 vs. HG + acetate + siRNA control, n = 3). (G) Effects of PKC signalling inhibition by Go 6983 (10 µmol/L) on restoration of Akt and AMPKα phosphorylation in podocytes treated by acetate (means ± SD, *P < 0.05 vs. Insulin; NS, not significant; n = 3). (H) Effects of PLC signalling inhibition mediated by U73122 (10 µmol/L) on restoration of Akt and AMPKα phosphorylation in podocytes treated by acetate (means ± SD, *P < 0.05 vs. Insulin; NS, not significant, n = 3).
Figure 6
Figure 6
The activation of GPR43 suppressed insulin signalling via downregulation of AMPKα activity. (A) Inhibitory effects of acetate on AMPKα phosphorylation in podocytes which were treated with different concentrations of acetate (3, 5, 10, 20 and 40 mmol/L) under the HG condition for 24h (means ± SD, *P < 0.05, **P < 0.01 vs. Ctrl, n = 3). (B) Podocytes were transfected with GPR43 siRNA for 12h and then stimulated with HG or HG plus acetate for 24h. The rescue effects of the GPR43 knockdown on AMPKα phosphorylation which was inhibited by acetate (means ± SD, *P < 0.05 vs. HG+ siRNA control, ##P < 0.01 vs. HG+acetate+ siRNA control, n = 3). (C) Podocytes were pretreated with a GPR43 inhibitor (GLPG0974, 10 µmol/L) for 12h and then stimulated with HG or HG plus acetate for 24h. The rescue effects of GPR43 inhibition on AMPKα phosphorylation which was inhibited by acetate (means ± SD, *P < 0.05 vs. Insulin, #P < 0.05 vs. Insulin + acetate, n = 3). (D) Western blotting analysis of AMPKα phosphorylation in renal tissue samples from the four groups of mice (Ctrl, GPR43 KO, DM and GPR43 KO+DM) (means ± SD, *P < 0.05 vs. Ctrl, #P < 0.05 vs. DM). (E) Effects of the activation AMPKα signalling mediated by AICAR (10 µmol/L) on restoration of insulin-induced Akt phosphorylation inhibited by acetate (means ± SD, *P < 0.05 vs. insulin, n = 3). (F) The effects of GPR43 knockdown on PKC and PLCγ1 phosphorylation in podocytes which was induced by acetate (mean ± SD, *P<0.05, ***P<0.001 vs. HG + siRNA control, ##P < 0.01, ###P < 0.001 vs. HG + acetate + siRNA control, n = 3). (G) Effects of PKC signalling inhibition by Go 6983 (10 µmol/L) on restoration of Akt and AMPKα phosphorylation in podocytes treated by acetate (means ± SD, *P < 0.05 vs. Insulin; NS, not significant; n = 3). (H) Effects of PLC signalling inhibition mediated by U73122 (10 µmol/L) on restoration of Akt and AMPKα phosphorylation in podocytes treated by acetate (means ± SD, *P < 0.05 vs. Insulin; NS, not significant, n = 3).

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