Supported Research

Lay Abstract

Role of proximal tubule (PT) sodium-glucose cotransporters (SGLT2) in DKD: The renal complications of diabetes include glomerular, vascular, and tubulo-interstitial processes characterized by an initial hyperfiltration, hypertrophy of the glomerulus and proximal tubule, expansion of the mesangial matrix (altered degradation or synthesis) leading to glomerular sclerosis, tubulointerstitial fibrosis, tubular lesions and atrophy. In addition to the classical disturbances implicated in the pathogenesis of DKD, namely altered hemodynamics and filtration barrier dysfunction, recent studies implicate proximal tubule transport and injury in the initiation and progression of DKD. This led to the discovery of SGLT2 inhibitors as important targets for anti-diabetic therapy. In diabetes, sodium retention occurs partly as a manifestation of excessive proximal tubule reabsorption and contributes to hyperfiltration, mediated by macula densa signaling. Proximal tubule sodium glucose cotransporters (SGLT) are a central component of this mechanism. SGLT2 transporters reabsorb over 90% of filtered glucose, whereas less than 10% is transported by SGLT1. SGLT2 levels are elevated in the diabetic proximal tubule, contributing to hyperglycemia, and are a key target for anti-hyperglycemic therapy. SGLT2 inhibitors reduce glomerular hyperfiltration in human DKD and reduce proteinuria. While hyperfiltration may be attenuated in diabetic patients, GFR ultimately normalizes, which is promising in terms of therapeutic usefulness of these drugs for CKD patients. Despite initial improvements in cardiac and renal outcomes in diabetes, the use of SGLT2 inhibitors like empagliflozin is limited to CKD patients with estimated GFR above 45 ml/min/1.73m2 since adverse renal events are possible. Though BP lowering effects may be beneficial, patients are at risk for postural hypotension and severe volume depletion especially when taking diuretics. Overview of the project: Diabetic kidney disease (DKD) is a common long-term complication of diabetes. In addition to the classical disturbances implicated in the pathogenesis of DKD, including hemodynamics and filtration barrier dysfunction, it also comprises proximal tubule transport and injury in the initiation and progression of DKD. Hypertension is commonly found in patients with diabetes and closely related with the development of chronic kidney disease and to end stage renal disease (ESRD). Together, diabetes and hypertension increase the mortality rate associated to cardiovascular complications. The sodium glucose co-transporter 2 (SGLT2), present in the S1, S2 segments of proximal tubular cells, is responsible for 90-95% of glucose reabsorption in normoglycemic conditions. In hyperglycemia, elevated blood glucose levels lead to SGLT2 overexpression as a compensatory mechanism. Thus, making SGLT2 inhibitors excellent therapeutic candidates for patients with diabetes type 2 (T2D). Gliflozins are a class of SGLT2 inhibitors primarily developed for glycemic control, later showing beneficial effects against cardiovascular diseases in diabetic patients, as well as renal injury in normoglycemic models. Dapagliflozin has shown to be protective against end-stage kidney disease, or even death against renal or cardiovascular diseases in patients with or without T2D. Our group has shown and published in J. Clin. Nephrol. that Empagliflozin improves albuminuria in type 2 diabetes mouse model. Moreover, clinical trials and animal studies have shown that SGLT2 inhibitors have nephroprotective properties even in normo-glycemic patients, indicating its overall therapeutic potential against kidney diseases.