Alk1 haploinsufficiency causes glomerular dysfunction and microalbuminuria in diabetic mice

• Published in: Scientific reports Vol. 10; no. 1; p. 13136
• Main Authors: Lora Gil, Cindy, Henley, Nathalie, Leblond, François A., Akla, Naoufal, Laurin, Louis-Philippe, Royal, Virginie, Gerarduzzi, Casimiro, Pichette, Vincent, Larrivée, Bruno
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-08-2020; Nature Publishing Group
• Subjects: 631/80/304; 692/4022/1585/2759/1419; Activin Receptors, Type II - genetics; Activin Receptors, Type II - metabolism; Albuminuria - genetics; Albuminuria - metabolism; Albuminuria - pathology; Animals; Apoptosis; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelium; Female; Haploinsufficiency; Humanities and Social Sciences; Humans; Hyperglycemia; Kidney diseases; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidneys; Male; Mice; Mice, Transgenic; Molecular modelling; multidisciplinary; Renal function; Rodents; Science; Science (multidisciplinary); Signal Transduction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-68515-z

Endothelial dysfunction has been shown to play an important role in the pathogenesis of glomerular damage during diabetic kidney disease (DKD). As such, a better understanding of the molecular mechanisms involved in glomerular endothelial dysfunctions could provide novel therapeutic strategies for the prevention of DKD. We have previously shown that Alk1/BMP9 signaling plays an important function to maintain vascular integrity in diabetic animals. As such, we evaluated the effects of Alk1 suppression on glomerular endothelial function in diabetic mice. In the present study, we used mice with conditional heterozygote deletion of Alk1 in the endothelium (Alk1ΔEC) to evaluate the role of Alk1 on kidney function during STZ-induced diabetes. DKD was investigated in diabetic control and Alk1ΔEC mice euthanized eight weeks after the onset of diabetes. We showed that Alk1 expression is reduced in the glomeruli of human DKD patients. While renal function was not altered in Alk1ΔEC non-diabetic mice, we showed that Alk1 haploinsufficiency in the glomerular endothelium leads to microalbuminuria, thickening of the glomerular basement membrane, glomerular apoptosis and podocyte loss in diabetic mice. These data suggest that Alk1 is important for the proper function of glomerular endothelial cells and that decreased Alk1 combined with chronic hyperglycemia can impair renal function.