The LIM and SH3 protein 1 (LASP1) regulates the synthesis and activation of A Disintegrin and Metalloproteinase 17 (ADAM17) in mesangial cells and is required for the profibrotic response to high glucose. 

New research findings have shown that its delegation protects against diabetic kidney disease in mice. 

According to the academics, targeting LASP1 may have therapeutic value as an indirect method of ADAM17 inhibition to inhibit fibrosis in diabetic kidney disease. 

Diabetic kidney disease is a prevalent complication of diabetes and is the leading cause of chronic kidney disease globally. 

Previous research has shown that the metalloprotease ADAM17 mediates the profibrotic response to high glucose in kidney mesangial cells. 

In this study, the scientists investigate regulation of the ADAM17 promoter region −2304/−1567, previously shown to be glucose responsive, for which regulatory factors have not yet been identified. 

ADAM17 promoter regulation, cell surface translocation and activation were assessed in primary rat mesangial cells using standard molecular biology techniques. 

Type 1 diabetes was induced in mice using streptozocin and kidney function and development of fibrosis were assessed after 24 weeks. Human and mouse kidneys were immunostained for LASP1.

In rat mesangial cells, LASP1 was identified as a regulator of the ADAM17 promoter in response to high glucose by mass spectrometry of nuclear lysate proteins binding to the −2304/−1567 promoter region, the findings have shown. 

In addition, the results have revealed that the knockdown of LASP1 prevented glucose-induced ADAM17 promoter activation and transcript and protein upregulation. 

According to the study, LASP1 nuclear localisation and regulation of ADAM17 promoter activity in high glucose required phosphorylation of LASP1 on S146 by protein kinase A, but not protein kinase G, and Y171 phosphorylation by Src kinase. 

The results stated: “LASP1 also regulated glucose-induced ADAM17 cell surface localisation and activation, dependent on its phosphorylation by Src and interaction with focal adhesion kinase. 

“Profibrotic responses to glucose were inhibited by LASP1 downregulation. In vivo, LASP1 expression was increased in the kidneys of type 1 diabetic mice and in kidneys of people with diabetic kidney disease. Mice with Lasp1 knockout showed attenuated development of diabetic kidney disease.”

Read the full study here – https://link.springer.com/article/10.1007/s00125-025-06662-6