Diabetes, Metabolic Syndrome and Obesity (Jan 2024)
Claudin-2 Mediates the Proximal Tubular Epithelial Cell–Fibroblast Crosstalk via Paracrine CTGF
Abstract
Congcong Guo,1– 4 Mingwen Jiao,5 Yuying Cui,1– 4 Pingjiang Li,6 Jinming Yao,1– 3 Jianjun Dong,7 Lin Liao1– 4 1Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 2Shandong Key Laboratory of Rheumatic Disease and Translational medicine, Shandong Institute of Nephrology, Jinan, Shandong, People’s Republic of China; 3Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 4Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 5Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 6Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 7Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Lin Liao, Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China, Tel +86 15168888260, Email [email protected] Jianjun Dong, Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China, Tel +86 13791122910, Email [email protected]: 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: proximal tubular epithelial cell, fibroblast, crosstalk, diabetic kidney disease, Claudin-2
