Claudin-2 Mediates the Proximal Tubular Epithelial Cell-Fibroblast Crosstalk via Paracrine CTGF

Congcong Guo; Mingwen Jiao; Yuying Cui; Pingjiang Li; Jinming Yao; Jianjun Dong; Lin Liao

doi:10.2147/DMSO.S432173

Claudin-2 Mediates the Proximal Tubular Epithelial Cell-Fibroblast Crosstalk via Paracrine CTGF

Diabetes Metab Syndr Obes. 2024 Jan 3:17:55-73. doi: 10.2147/DMSO.S432173. eCollection 2024.

Authors

Congcong Guo^{1

2

3

4}, Mingwen Jiao⁵, Yuying Cui^{1

2

3

4}, Pingjiang Li⁶, Jinming Yao^{1

2

3}, Jianjun Dong⁷, Lin Liao^{1

2

3

4}

Affiliations

¹ Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People's Republic of China.
² Shandong Key Laboratory of Rheumatic Disease and Translational medicine, Shandong Institute of Nephrology, Jinan, Shandong, People's Republic of China.
³ Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People's Republic of China.
⁴ Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People's Republic of China.
⁵ Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People's Republic of China.
⁶ Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.
⁷ Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.

Abstract

Purpose: Proximal tubular epithelial cell (PTEC) is vulnerable to injury in diabetic kidney disease (DKD) due to high energy expenditure. The injured PTECs-derived profibrotic factors are thought to be driving forces in tubulointerstitial fibrosis (TIF) as they activate surrounding fibroblasts. However, the mechanisms remain unclear.

Methods: The diabetes with uninephrectomy (DKD) rats were used to evaluated renal histological changes and the expression of Claudin-2 by immunofluorescence staining. Then, Claudin-2 expression in PTECs were modulated and subsequently determined the proliferation and activation of fibroblasts by building a transwell co-culture system in normal glucose (NG)or high glucose (HG) condition.

Results: Decreased expression of Claudin-2 in PTECs accompanied by tight junction disruption and increased interstitial fibrosis, were detected in DKD rats. In vitro, downregulated Claudin-2 in PTECs promoted proliferation and activation of fibroblasts, which coincided with elevated expression of profibrotic connective tissue growth factor (CTGF) in PTECs. Silenced CTGF inhibited the profibrotic of PTECs via Claudin-2 inhibition. Fibroblasts co-cultured with PTECs transitioned more to myofibroblasts and generated extracellular matrix (ECM) significantly in response to high glucose (HG) stimulation whereas overexpression of Claudin-2 in PTECs reversed the above results. Upregulating CTGF disrupted the beneficial anti-fibrosis effects obtained by overexpression of Claudin-2 in HG condition.

Conclusion: Our study suggested that Claudin-2 in PTECs, a key mediator of paracellular cation and water transport, promotes the activation and proliferation of surrounding fibroblasts significantly via CTGF in a paracrine manner.

Keywords: Claudin-2; crosstalk; diabetic kidney disease; fibroblast; proximal tubular epithelial cell.

Grants and funding

This work was funded by National Natural Science Foundation of China Grants (NO.82170847, 82105044), key project of Shandong Provincial Natural Science Foundation of China Grants (NO. ZR2020KH004); Shandong Provincial Natural Science Foundation of China Grants (No. ZR 2020QH310).