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. 2023 Dec 5;24(1):361.
doi: 10.1186/s12882-023-03415-8.

IL-33/ST2L signaling alleviates diabetic nephropathy by regulating endoplasmic reticulum stress and apoptosis

Teng Liu  1   2 , Yu-Qing Jin  1 , Qi Wang  1 , Cong-Hui Jia  1 , Wei-Yan Ren  1 , Jia-Yi Liu  1 , Lei Yang #  3 , Hong-Min Luo #  4
Affiliations

IL-33/ST2L signaling alleviates diabetic nephropathy by regulating endoplasmic reticulum stress and apoptosis

Teng Liu et al. BMC Nephrol. .

Abstract

Objective: Diabetic nephropathy (DN) is a serious chronic complication of diabetes mellitus (DM). Endoplasmic reticulum (ER) stress is an important factor in the regulation of pathological processes in DN, and excessive ER stress can lead to apoptosis. Although the IL-33/ST2 axis is known to be involved in diabetic kidney disease or related nephropathy, its role and molecular mechanisms remain poorly understood in terms of DN. The purpose of this study was to investigate the effects of IL-33/ST2 signaling on DN and to characterize the roles that ER stress and apoptosis play in DN.

Methods: To investigate this study, mice were randomly assigned into DN (induced by 0.1% STZ) and Control groups. Biochemical indices (FBG, BUN, UPR, UCE) were measured in serum and urine samples to reflect blood glucose and kidney damage. Quantitative real-time PCR, western blot, and immunofluorescence were used to assess gene and protein expression of the IL-33/ST2 axis and ER stress relative signaling molecule. Apoptosis was analyzed by flow cytometry.

Results: IL-33 levels are significantly increased in the kidneys of patients and mice with DN. Double immunofluorescence staining showed that IL-33 colocalized with CD31-positive endothelial cells. Treatment with IL-33 attenuated kidney injury in Streptozotocin (STZ)-treated mice. In vitro, we showed that IL-33 attenuated ER stress and apoptosis in glomerular endothelial cells. However, sST2 treatment significantly reversed these effects of IL-33.

Conclusion: Together, these data suggest that IL-33/ST2 signaling mitigates STZ-induced renal damage, partly at least, by suppressing ER stress and apoptosis. Therefore, IL-33 may be an effective therapeutic target in DN.

Keywords: Apoptosis; Diabetic nephropathy; Endoplasmic reticulum stress; IL-33; ST2.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The mechanism diagram for this article
Fig. 2
Fig. 2
The expression of IL-33 and sST2 in DN. (A) Identification of IL-33 and sST2 from GEO datasets (GSE96804) in heath control (HC; n = 19) and DN patients (n = 42). (B) Quantitative real-time PCR analysis of IL-33 and sST2 in STZ-induced mice (n = 6 each). The expression level in the Control group was assigned a value of 1. Data are expressed as means ± SEM. **p < 0.01. (C) Double immunostaining with anti-CD31 and anti-IL-33 in kidney sections. Scale bars = 50 μm. Fluorescence colocalization ratio analysis showed that the expression of IL33 in glomeruli was significantly increased in STZ mice
Fig. 3
Fig. 3
Body weight, Fast blood glucose, and biochemical indices in Control, STZ, STZ + IL-33, and STZ + sST2 mice. Body weight (A) and Fast blood glucose (B) was measured before sacrificed and expressed as the mean ± SEM. n = 6 in each group. (C) Serum blood urea nitrogen level. (D) UPC ratio: urine protein / urine creatinine. Data are expressed as means ± SEM. n = 5 in each group. *p < 0.05, **p < 0.01, ***p < 0.001, **** p < 0.0001. (E) HE staining of renal tissue. Scale bars = 50 μm
Fig. 4
Fig. 4
ER stress-related factors in Control, STZ, STZ + IL-33, and STZ + sST2 mice. (A) Quantitative real-time PCR analysis of ATF6, PERK and IRE1 in renal tissue (n = 6 each). The expression level in the Control group was assigned a value of 1. Data are expressed as means ± SEM. *p < 0.05, **p < 0.01. (B) Immunohistochemical staining of CHOP and caspase3 in renal tissue. Scale bars = 50 μm
Fig. 5
Fig. 5
Effects of IL-33 and ST2 on ER stress and apoptosis in MGECs exposed to HG. (A) Western blots of MGECs showing the effect of IL-33 and ST2 exposed to HG. GAPDH was used as a loading control. Quantification relative to GADPH level. Results are representative of 1 in 3 replications. Data are means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, **** p < 0.0001. (B) Flow cytometry analysis of apoptosis in MGECs. Representative images and apoptotic rates in cells show that a high concentration of IL-33 stimulation can reduce apoptosis. UR = late apoptotic cells; LR = early apoptotic cells; UR + LR = total apoptotic cells. The experiment was repeated at least three times. Data are means ± SEM. **p < 0.01, ***p < 0.001
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