Group 2 Innate Lymphoid Cells Participate in Renal Fibrosis in Diabetic Kidney Disease Partly via TGF-β1 Signal Pathway

Abstract

Aim. To explore the role of group 2 innate lymphoid cells (ILC2s) in the pathogenesis of renal fibrosis in diabetic kidney disease (DKD). Methods. The proportion of ILC2s and the levels of Th2 cytokines (IL-4, IL-5, and IL-13) in the peripheral blood of normal control subjects (NC) or patients with type 2 diabetes mellitus (DM), early diabetic kidney disease (DKD1), or late diabetic kidney disease (DKD2) were analyzed by flow cytometry and ELISA. The expression of transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen1, IL-4Rα, and IL-13Rα1 in renal tubular epithelial cells (HK-2) induced by IL-4, IL-13, or high glucose was analyzed by ELISA or qPCR. Results. The proportion of ILC2s and the levels of IL-4, IL-5, and IL-13 were significantly increased in DKD patients and were positively correlated with the severity of DKD (P<0.05). The expression of TGF-β1, FN, and collagen1 was significantly upregulated in HK-2 cells induced by IL-4 or IL-13 (P<0.05). Moreover, the IL-4Rα and IL-13Rα1 mRNA in HK2 cells were increased followed by high glucose alone or combined with IL-4 or IL-13, but the differences were not statistically significant (P>0.05). However, compared with high-glucose stimulation alone, the expression of TGF-β1, FN, and collagen1 was significantly increased in HK-2 cells induced by high glucose combined with IL-4 or IL-13 (P<0.05). Conclusions. ILC2s may participate in renal fibrosis in DKD partly via TGF-β1 signal pathway.

Effect and Mechanism of TL1A Expression on Epithelial-Mesenchymal Transition during Chronic Colitis-Related Intestinal Fibrosis

“…The fourth ECCO guidelines state that IL-13 activates the TGF- β 1/Smad3 pathway as the central process in intestinal fibrosis formation [ 21 ]. It is reported that IL-4 and IL-13 can synergize with high glucose to promote the expression of TGF- β 1, FN, and collagen I in cultured HK-2 cells, indicating that the secretion of Th2 cytokines (IL-4 and IL-13) and the upregulated expression of TGF- β 1 are key factors in the development of renal fibrosis [ 39 ]. Another study showed that IL-13 induces fibrosis through the activation of TGF- β 1, and the synergistic effect of IL-13 and TGF- β 1 may increase the expression of eotaxin in human fibroblast [ 40 ].…”

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

“…A study by Wang et al indicated that adipose tissue-resident ILC1s, via the production of IFN-γ, promote tissue fibrosis and induce diabetes in obese individuals (185). Liu et al have demonstrated that the numbers of ILC2s as well as serum cytokine levels of IL-4, IL-5, and IL-13 are significantly elevated in diabetic kidney disease patients and have a positive correlation with disease severity (186). They further demonstrated that ILC2s, through the TGF-β1 signaling pathway, are involved in renal fibrosis seen in diabetic kidney disease (184).…”

The Roles of Kidney-Resident ILC2 in Renal Inflammation and Fibrosis

“…A recent study indicated that blood ILC2s are upregulated in ESRD patients (62); however, it is unclear if this elevation is related to ESRD pathogenesis. Moreover, it has also been reported that changes of blood ILC correlate with the severity of DN and LN (63,64). Further investigation is required to determine whether human renal ILC2s are friend or foe in kidney diseases.…”

“…In addition, Liu et al. have been reported that ILC2 was negatively correlated with eGFR level in diabetic kidney disease patient with promoting renal fibrosis ( 63 ). Although it is not well understood whether Areg produced from ILC2 contribute to progress renal fibrosis, Areg expression is required for fibrosis induced by TGF-b overproduction.…”