title: Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.
abstract: Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.
authors.affiliation: Nephrology Division, Second University of Naples-Med School, Naples, Italy. Electronic address: luca.denicola@unina2.it.
authors.forename: Luca
authors.initials: L
authors.lastname: De Nicola
authors.affiliation: Department of Medicine, Veterans Administration San Diego Healthcare System-University of California at San Diego Medical School, San Diego, CA.
authors.forename: Francis B
authors.initials: FB
authors.lastname: Gabbai
authors.affiliation: Nephrology Division, Second University of Naples-Med School, Naples, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Liberti
authors.affiliation: Nephrology Division, Second University of Naples-Med School, Naples, Italy.
authors.forename: Adelia
authors.initials: A
authors.lastname: Sagliocca
authors.affiliation: Nephrology Division, Second University of Naples-Med School, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Conte
authors.affiliation: Nephrology Division, Second University of Naples-Med School, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Minutolo
mesh_terms: D000818:Animals; D048909:Diabetes Complications / Q000150:complications / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000503:physiopathology*; D012084:Renin-Angiotensin System / Q000502:physiology; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
keywords: Diabetes mellitus (DM); SGLT2 inhibitor; canagliflozin; dapagliflozin; diabetic nephropathy (DN); glomerular filtration rate (GFR); hyperfiltration; proximal tubule; sodium/glucose cotransport; sodium/glucose cotransporter 2 (SGLT2)