Sodium-Glucose Transporter Type 2 (SGLT2) Inhibitor for Diabetic Kidney

In diabetes, both activation of renin-angiotensin system and glomerular hyperfiltration are seen even before the development of diabetic nephropathy. Glomerular hyperfiltration depends on glomerular hypertension sue to pathophysiological afferent arteriolar dilation. Tubular hypothesis has been proposed more than a decade ago to explain the above in type1 diabetes. Recently, clinical evidences have been accumulated to support tubular hypothesis functioning in type2 diabetes. In addition to intrinsic renal hemodynamic physiology, the key molecule for tubular hypothesis is sodium glucose co-transporter in proximal tubules. Thus, application of sodium glucose co-transporter for diabetes may provide a break-through for the management of diabetes in preventing the development of nephropathy. Recently, SGLT2 inhibitors, a new anti-diabetic drug, have become available for clinical use. This drug is superior to classical anti-diabetic medications such as sulfonyl urea and metoformin, facilitating weight loss and decreasing systolic blood pressure [1]. In addition to their excellent anti-diabetic actions, they could prevent the development of diabetic nephropathy. Potential renal hemodynamic mechanisms for renal protection by this medication are reviewed. TUBULOGLOMERULAR FEEDBACK (TGF) Macula densa cell releases ATP into the interstitium when it reabsorbs sodium chloride delivered by tubular flow [2]. On the one hand, ATP released from macula densa binds to ATP receptor located on extraglomerular mesangial cells to induce membrane depolarization and/or an increase in cytosolic calcium. These signals travel to neighboring mesangial cells through gap junctions, and finally the signals are transduced to afferent arteriolar myocytes through gap junction. Gap junction constitutes an important intercellular communication tool. Indeed, the inhibiting the function of connexin (Cx37 or Cx40), which compose of gap junction, elicits both suppression of TGF-dependent autoregulation and RAS activation. There is a possibility that ATP secreted from macula densa diffuses to afferent arteriolar myocytes and directly interacts with ATP receptors to induce afferent arteriolar constriction. On the other hand, ATP is degraded to adenosine by nucleotidase on extra glomerular mesangial cells, and subsequently adenosine binds to its specific receptor on afferent arteriolar myocytes to induce constriction. TUBULAR HYPOTHESIS From the renal hemodynamic point of view, diabetic nephropathy is characterized by glomerular hypertension and hyperfiltration from its early stage. Abnormal afferent arteriolar dilation is the basis for experimental diabetic nephropathy [3]. In non-diabetic chronic kidney disease, single nephron glomerular hypertension and hyperfiltration occur in remnant nephrons to suffice the function of lost glomeruli due to its underlying renal disease. Thus, glomerular hyperfiltration starts when renal injury has progressed to some extent in non-diabetic chronic kidney diseases. However, all nephrons in diabetes show glomerular hypertension and hyperfiltration before microalbuminuria will be developed [4]. Tubular hypothesis is based on physiological responses to hyperglycemia and its mechanisms are following [5]. In diabetes, hyperglycemia results in high glucose concentration in ultrafiltrate in Bowman capsule. Although proximal tubules reuptake most amounts of filtered glucose, glucose exceeding the capacity of tubular reuptake excretes into urine (glycosuria). Since proximal tubule possesses sodium glucose co-transporter type 1 (SGLT1) and SGLT2, glucose is up-taken together with sodium through these transporters. Then, the reuptake of sodium chloride is increased in hyperglycemic condition, which is considered as a cause of salt sensitive hypertension in diabetes. Furthermore, the delivery of sodium and chloride to macula densa is decreased by enhanced reuptake by proximal tubules (figure 1). A reduced delivery to macula densa dilates the afferent arteriole by removing constrictor signals from tubuloglomerular feedback (TGF), thereby inducing glomerular hypertension and hyperfiltration. Moreover, TGF signal from macula densa inhibits Central Takenaka (2014) Email: J Clin Nephrol Res 1(1): 1004 (2014) 2/3 renin release. Again, a reduced delivery to macula densa during hyperglycemia (due to increased proximal tubular absorption) removes TGF signal, thereby releasing renin and activate reninangiotensin system (RAS) which constricts efferent arterioles, further worsening glomerular hypertension [2].