Korean J Physiol Pharmacol.  2022 Nov;26(6):427-438. 10.4196/kjpp.2022.26.6.427.

The role of discoid domain receptor 1 on renal tubular epithelial pyroptosis in diabetic nephropathy

• Zhao W
• He C
• Jiang J
• Zhao Z
• Yuan H
• Wang F
• Shen B

• KMID: 2534519
• DOI: http://doi.org/10.4196/kjpp.2022.26.6.427

Abstract

Pyroptosis, a form of cell death associated with inflammation, is known to be involved in diabetic nephropathy (DN), and discoid domain receptor 1 (DDR1), an inflammatory regulatory protein, is reported to be associated with diabetes. However, the mechanism underlying DDR1 regulation and pyroptosis in DN remains unknown. We aimed to investigate the effect of DDR1 on renal tubular epithelial cell pyroptosis and the mechanism underlying DN. In this study, we used high glucose (HG)-treated HK-2 cells and rats with a single intraperitoneal injection of streptozotocin as DN models. Subsequently, the expression of pyroptosis-related proteins (cleaved caspase-1, GSDMD-N, Interleukin-1β [IL-1β], and interleukin-18 [IL-18]), DDR1, phosphorylated NF-κB (p-NF-κB), and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes were determined through Western blotting. IL-1β and IL-18 levels were determined using ELISA. The rate of pyroptosis was assessed by propidium iodide (PI) staining. The results revealed upregulated expression of pyroptosisrelated proteins and increased concentration of IL-1β and IL-18, accompanied by DDR1, p-NF-κB, and NLRP3 upregulation in DN rat kidney tissues and HG-treated HK-2 cells. Moreover, DDR1 knockdown in the background of HG treatment resulted in inhibited expression of pyroptosis-related proteins and attenuation of IL-1β and IL-18 production and PI-positive cell frequency via the NF-κB/NLRP3 pathway in HK-2 cells. However, NLRP3 overexpression reversed the effect of DDR1 knockdown on pyroptosis. In conclusion, we demonstrated that DDR1 may be associated with pyroptosis, and DDR1 knockdown inhibited HG-induced renal tubular epithelial cell pyroptosis. The NF-κB/NLRP3 pathway is probably involved in the underlying mechanism of these findings.

Keyword

Diabetic nephropathy; Discoid domain receptor 1; NLR family pyrin domain-containing 3; Nuclear factor kappa B; Pyroptosis

Figure

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  Fig. 1 Changes in the kidney function and morphology in diabetic rats. A rat model wherein streptozotocin (STZ) was used to induce diabetic nephropathy (DN). (A) H&E staining to observe the morphological characteristics of the kidney (scale bar 50 μm, ×400; scale bar 200 μm, ×100) magnifications, (B) Albumin/creatinine ratio. (C) Plasma cystatin-C levels. (D) Glomerular volume. (E) Mesangial area. (F) Tuft area. Data are presented as mean ± SEM from 6 rats. Compared to control, **p < 0.01.

• 

  Fig. 2 In vivo and in vitro expression of pyroptosis-related proteins. (A) Bands corresponding to the expression of pyroptosis-related proteins (caspase-1 p45, cleaved caspase-1, interleukin [IL]-1β, IL-18, gasdermin D [GSDMD], and GSDMD-N) in the kidneys of diabetic nephropathy (DN) rats. (B) Quantification of the bands observed in (A). (C) Concentration of IL-1β in rat plasma. (D) Concentration of IL-18 in rat plasma. (E) Bands corresponding to the expression of pyroptosis-related proteins (caspase-1 p45, cleaved caspase-1, IL-1β, IL-18, GSDMD, and GSDMD-N) in high glucose (HG)-treated HK-2 cells. (F) Quantification of the bands observed in (E). (G) Concentration of IL-1β in HK-2 cell supernatant. (H) Concentration of IL-18 in HK-2 cell supernatant. Data are presented as mean ± SEM from 6 rats and 3 replicated cell experiments. Compared to control, *p < 0.05, **p < 0.01.

• 

  Fig. 3 In vivo and in vitro expression of discoid domain receptor 1 (DDR1). (A) DDR1 expression in the kidneys of diabetic nephropathy (DN) rats. (B) DDR1 expression in high glucose (HG)-treated HK-2 cells. Data are presented as mean protein in the kidneys of DN rats and HG-treated HK-2 cells. Data are presented as mean ± SEM from 6 rats and 3 replicated cell experiments. Compared to control, **p < 0.01.

• 

  Fig. 4 Effect of discoid domain receptor 1 (DDR1) knockdown on HK-2 cell pyroptosis. (A) Bands corresponding to the expression of DDR1 in the background of transfection with siDDR1. (B) Quantification of the band observed in (B). (C) Propidium iodide (PI) staining was used to analyze HK-2 cell death (scale bar: 200 μm). (D) Percentage HK-2 cell pyroptosis. (E) Bands corresponding to the expression of pyroptosis-related proteins (caspase-1 p45, cleaved caspase-1, interleukin [IL]-1β, IL-18, gasdermin D [GSDMD], and GSDMD-N). (F) Quantification of the bands observed in (E). (G) The concentration of IL-1β in HK-2 cell supernatant. (H) The concentration of IL-18 in HK-2 cell supernatant. Data are presented as mean ± SEM from 3 replicated cell experiments. Compared to high glucose (HG), *p < 0.05, **p < 0.01.

• 

  Fig. 5 Discoid domain receptor 1 (DDR1) knockdown resulted in the downregulation of the nuclear transcription factor-κB (NF-κB)/NLR family pyrin domain-containing 3 (NLRP3) pathway intermediaries at the protein level. (A) Bands corresponding to the expression of phosphorylated NF-κB (p-NF-κB) and NF-κB in the kidneys of DN rats. (B) Bands corresponding to the expression of NLRP3 in the kidneys of diabetic nephropathy (DN) rats. (C) Bands corresponding to the expression of p-NF-κB and NF-κB in HK-2 cells. (D) Bands corresponding to the expression of NLRP3 in HK-2 cells. Data are presented as mean ± SEM from 6 rats and 3 replicated cell experiments. Compared to control, **p < 0.01. Compared to high glucose (HG), #p < 0.05, ##p < 0.01.

• 

  Fig. 6 NLR family pyrin domain-containing 3 (NLRP3) reversed the discoid domain receptor 1 (DDR1) knockdown‒mediated downregulation of the nuclear transcription factor-κB (NF-κB)/NLRP3 pathway intermediaries at the transcript level (assessed using RT-qPCR). Transcript-level expression of (A) NLRP3, (B) NF-κB, (C) caspase-1, (D) gasdermin D (GSDMD), (E) interleukin (IL)-1β, (F) IL-18. Data are presented as mean ± SEM from 3 replicated cell experiments. Compared to control **p < 0.01. Compared to high glucose (HG), ##p < 0.01. Compared to siDDR1, &&p < 0.01.

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