Physical and functional interaction between NHE3 and SGLT2 in renal proximal tubule: physiological, physiopathological and therapeutic implications

Abstract

NHE3 is the most abundant Na+/H+ exchanger isoform at the apical membrane of the proximal tubule, being responsible for the majority of the filtered NaCl and NaHCO3. As such, this NHE isoform plays an essential role in volume homeostasis, acid-base homeostasis, and in determining systemic blood pressure levels. Cummulative evidence indicates that hormones, compounds associated with regulation of glucose metabolism, as well as experimental Diabetes and antidiabetic agents affect the activity of NHE3 inthe proximal renal tubule. Additionally, our recent findings that the glucagon-likepeptide-1 incretin hormone (GLP-1) exert a physiological effect on renal sodium handling, in part via NHE3 activity inhibition, reinforces the existence of a relationship between glucose homeostasis and regulation of salt balance and extracellular volume. Glucose is entirely reabsorbed in the proximal tubule by means of the sodium-dependent glucose transporters, SGLT1 and SGLT2. Recent published results from our laboratory indicate that the specific SGLT2 inhibitor empagliflozin reduces NHE3activity and that only SGLT2, but not SGLT1, co-localizes with NHE3 on the apical membrane of the renal proximal tubule. SGLT2 inhibitors are the newest class of antihyperglycemic agents and the only antidiabetic drug that reduce cardiovascular events. In the light of the above, the main objectives of this project are: to test the hypothesis that NHE3 and SGLT2 are physically associated in the proximal renal tubule; elucidate the possible mechanism by which the SGLT2 inhibitor inhibits NHE3 activity; and investigate the pathophysiological and therapeutic importance of the physical and/or functional association of NHE3 with SGLT2 in diseases characterized by disorders ofglycemic and/or cardiovascular homeostasis, such as Type 2 Diabetes Mellitus (DM2), Hypertension and Congestive Heart Failure. Given the prevalence of DM2 and the beneficial glycemic and cardiovascular effects of SGLT2 inhibitors in this population, itis possible that millions of individuals will take these medicines in the coming years.These aspects justify the effort to seek greater knowledge about the physiological interactions of SGLT2 and the actions of its inhibitors in the proximal renal tubule. (AU)