Galectin‐1 is a new fibrosis protein in type 1 and type 2 diabetes

Abstract

Chronic exposure of tubular renal cells to high glucose contributes to tubulointerstitial changes in diabetic nephropathy. In the present study, we identified a new fibrosis gene called galectin-1 (Gal-1), which is highly expressed in tubular cells of kidneys of type 1 and type 2 diabetic mouse models. Gal-1 protein and mRNA expression showed significant increase in kidney cortex of heterozygous Akita and db/db mice compared with wild-type mice. Mouse proximal tubular cells exposed to high glucose showed significant increase in phosphorylation of Akt and Gal-1. We cloned Gal-1 promoter and identified the transcription factor AP4 as binding to the Gal-1 promoter to up-regulate its function. Transfection of cells with plasmid carrying mutations in the binding sites of AP4 to Gal-1 promoter resulted in decreased protein function of Gal-1. In addition, inhibition of Gal-1 by OTX-008 showed significant decrease in p-Akt/AP4 and protein-promoter activity of Gal-1 and fibronectin. Moreover, down-regulation of AP4 by small interfering RNA resulted in a significant decrease in protein expression and promoter activity of Gal-1. We found that kidney of Gal-1 mice express very low levels of fibronectin protein. In summary, Gal-1 is highly expressed in kidneys of type 1 and 2 diabetic mice, and AP4 is a major transcription factor that activates Gal-1 under hyperglycemia. Inhibition of Gal-1 by OTX-008 blocks activation of Akt and prevents accumulation of Gal-1, suggesting a novel role of Gal-1 inhibitor as a possible therapeutic target to treat renal fibrosis in diabetes.-Al-Obaidi, N., Mohan, S., Liang, S., Zhao, Z., Nayak, B. K., Li, B., Sriramarao, P., Habib, S. L. Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes.

Increased circulating galectin-1 levels are associated with the progression of kidney function decline in patients undergoing coronary angiography

“…Multivalent interactions between galectin-1 and glycoproteins in the extracellular matrix contribute to cancer metastasis. A few in vitro and animal studies have mentioned the potential link between galectin-1 and kidney diseases [20][21][22][25][26][27][28] , but no previous clinical report has described an association between the galectin-1 level and CKD.…”

“…Several groups have postulated the existence of mechanisms relating galectin-1 to CKD 20 , especially in the context of diabetes 21,22 . Increased galectin-1 expression has been reported in diabetes 19 , diabetic retinopathy 29 and diabetic nephropathy 21,22 . Galectin-1 has been shown to regulate podocin production and damage, and diabetic nephropathy progression, in podocytes 22 .…”

“…Increased galectin-1 expression has been reported in diabetes 19 , diabetic retinopathy 29 and diabetic nephropathy 21,22 . Galectin-1 has been shown to regulate podocin production and damage, and diabetic nephropathy progression, in podocytes 22 . In addition, recent evidence has revealed that galectin-1 is a fibrosis protein that is highly expressed in the kidneys of mice with types 1 and 2 diabetes, and activated in proximal tubular epithelial cells under high-glucose conditions 22 .…”

“…An in vitro study implicated galectin-1 in diabetic nephropathy, as seen in human podocytes in high-glucose culture 21 . Furthermore, galectin-1 was reported to be a new fibrosis protein and potential treatment target in the context of diabetic nephropathy 22 . However, whether the serum galectin-1 level can predict CIN and kidney function decline in patients undergoing CAG remains unclear.…”

Elevated level of Galectin-1 in bronchoalveolar lavage of patients with idiopathic pulmonary fibrosis

“…Inhibition of galectin-1 has also been proposed as a possible treatment for renal fibrosis in diabetics, for several types of cancer and for HIVinfected cells (Al-Obaidi et al, 2019;Goud et al, 2019b;Chang et al, 2017).…”