huSLC5A2 Mouse

The SLC5A2 gene, also known as SGLT2, encodes sodium-glucose cotransporter 2, a member of the solute carrier family 5 and a low-affinity, high-capacity sodium-glucose cotransporter. It is highly expressed in the brush border of the early segment (S1 segment) of the renal proximal tubule, where it is responsible for reabsorbing approximately 90% of glucose from the glomerular filtrate ^[1-2]. In glucose homeostasis, the SGLT2 protein prevents energy loss through urine by efficiently reabsorbing filtered glucose; inhibiting its function can directly induce glucosuria, thereby lowering blood glucose ^[3]. SGLT2 overexpression or enhanced activity is closely associated with the progression of type 2 diabetes, chronic kidney disease, and heart failure, making it an important therapeutic target: in type 2 diabetes, hyperglycemia leads to a significant increase in the glucose load filtered by the glomeruli, and the proximal tubule undergoes compensatory hypertrophy and hyperplasia, with SGLT2-mediated glucose and sodium reabsorptive capacity subsequently enhanced, thereby accelerating diabetic nephropathy progression ^[4]; in chronic kidney disease, single-nephron hyperfiltration in remnant nephrons further exacerbates the SGLT2-dependent reabsorptive burden, forming a vicious cycle ^[5]; in heart failure, increased volume load, sympathetic activation, and elevated angiotensin II can also upregulate SGLT2 activity, promoting proximal sodium reabsorption and aggravating fluid and sodium retention as well as cardiorenal burden ^[6]. Loss-of-function mutations in SLC5A2 cause familial renal glucosuria, characterized by persistent isolated glucosuria in the presence of normal blood glucose levels, generally with a favorable prognosis, but may be accompanied by varying degrees of sodium loss and volume changes ^[7]. In addition to improving glycemic control, SGLT2 inhibitors also exert weight reduction, blood pressure lowering, and significant cardiorenal protective effects ^[3,6].

The huSLC5A2 mouse is a humanized mouse model generated by gene editing, in which the sequence from exon 1 through part of intron 12 of the mouse Slc5a2 gene was replaced with the sequence from exon 1 through exon 14 of the human SLC5A2 gene, together with the SV40 late pA sequence. This model can be used for mechanistic studies of type 2 diabetes, chronic kidney disease, heart failure, familial renal glucosuria, and other related diseases, as well as for the screening, efficacy evaluation, and preclinical in vivo studies of small molecule inhibitors, antibodies, small nucleic acid drugs, and other therapeutics targeting human SGLT2.