The Sodium-glucose cotransporter 2 (SGLT2), a key type of Na Glucose Transporter, plays a vital role in glucose reabsorption within the kidneys. Primarily located in the early proximal tubule, SGLT2 is responsible for the high-capacity uptake of glucose from the glomerular filtrate back into the bloodstream. This mechanism is crucial for maintaining glucose homeostasis in the body. Given its significant role in renal glucose handling, SGLT2 has become a therapeutic target, with SGLT2 inhibitors developed as a novel class of antidiabetic drugs. To further understand the specific contributions of SGLT2 to glucose control and kidney function, particularly in diabetic conditions, researchers have utilized animal models, such as gene-targeted Sglt2 knockout mice.
A study employing these Sglt2 knockout (Sglt2(-/-)) mice investigated the impact of SGLT2 absence on blood glucose regulation, glomerular hyperfiltration, kidney growth, and various markers associated with renal growth and injury. The study induced low-dose streptozotocin (STZ) diabetes in both Sglt2(-/-) mice and wild-type (WT) mice and assessed these parameters at 5 weeks and 4.5 months post-induction. Interestingly, the absence of SGLT2 did not significantly alter the renal mRNA expression of other glucose transporters, including SGLT1, NaGLT1, GLUT1, or GLUT2, in response to STZ treatment. This suggests a specific and non-compensatory role for SGLT2 in renal glucose transport under these conditions.
When diabetes was induced via STZ, blood glucose levels increased in both Sglt2(-/-) and WT mice. However, the increase was less pronounced in the Sglt2(-/-) group compared to the WT group (approximately 300 mg/dl vs. 470 mg/dl). This finding underscores the contribution of SGLT2 to overall hyperglycemia in STZ-induced diabetes. Despite the reduced hyperglycemia, both genotypes exhibited similar levels of glucosuria (glucose in urine), as well as comparable increases in food and fluid intake, common symptoms of diabetes. Notably, the absence of SGLT2 proved protective against STZ-induced glomerular hyperfiltration, a condition characterized by an excessive filtration rate in the kidneys, which can contribute to kidney damage. However, SGLT2 knockout did not prevent the increase in kidney weight observed in diabetic conditions.
Further analysis focused on markers of renal stress and damage. The study revealed that knocking out SGLT2 attenuated the STZ-induced accumulation of p62/sequestosome in the kidneys. p62 is an indicator of impaired autophagy, a cellular process for clearing damaged components. This suggests that SGLT2 may play a role in autophagy dysfunction in diabetic kidneys. Conversely, the absence of SGLT2 did not mitigate the STZ-induced increase in renal expression of markers associated with kidney growth (p27 and proliferating cell nuclear antigen), oxidative stress (NADPH oxidases 2 and 4 and heme oxygenase-1), inflammation (interleukin-6 and monocyte chemoattractant protein-1), fibrosis (fibronectin and Sirius red-sensitive tubulointerstitial collagen accumulation), or injury (renal/urinary neutrophil gelatinase-associated lipocalin). These findings indicate that while SGLT2 contributes to hyperglycemia and glomerular hyperfiltration, it is not a primary driver of renal growth, injury, inflammation, or fibrosis in this model of STZ-induced diabetes. Furthermore, SGLT2 deficiency did not increase susceptibility to ascending urinary tract infections in either non-diabetic or diabetic mice, addressing a potential safety concern related to SGLT2 inhibition.
In conclusion, this research highlights that SGLT2, a key Na glucose transporter in the kidney, is a significant determinant of hyperglycemia and glomerular hyperfiltration in the context of STZ-induced diabetes mellitus. However, the study suggests that SGLT2 is not essential for the development of renal growth and markers of renal injury, inflammation, and fibrosis in this particular diabetic model. These findings contribute to a deeper understanding of the specific roles of SGLT2 in diabetic kidney disease and have implications for the therapeutic use of SGLT2 inhibitors.
