Research Article Details

Article ID: A52310
PMID: 28811292
Source: Am J Physiol Endocrinol Metab
Title: Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes.
Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic oral agents indicating promising effects on cardiovascular and renal end points. However, the renoprotective effects of SGLT2 inhibitors are not fully understood. Also, metabolic effects of SGLT2 inhibition on other organ systems, such as effects on hepatic steatosis, are not fully understood. This study sought to address these questions by treating 18-wk-old uninephrectomized db/db mice with the selective SGLT2 inhibitor dapagliflozin. Untreated db/db mice developed progressive albuminuria, glomerular mesangial matrix expansion, and fatty liver associated with increased renal expression of TGF&#946;1, PAI-1, type IV collagen and fibronectin, and liver deposition of fibronectin, type I and III collagen, and laminin. Treatment with dapagliflozin (1 mg&#183;kg-1&#183;day-1) via gel diet from 18 to 22 wk of age not only reduced blood glucose (371.14 &#177; 55.02 mg/dl in treated db/db vs. 573.53 &#177; 21.73 mg/dl in untreated db/db, P < 0.05) and Hb A1c levels (9.47 &#177; 0.79% in treated db/db vs. 12.1 &#177; 0.73% in untreated db/db, P < 0.05) but also ameliorated the increases in albuminuria and markers of glomerulosclerosis and liver injury seen in untreated db/db mice. Furthermore, both renal expressions of NF-kB p65, MCP-1, Nox4, Nox2, and p47phox and urine TBARS levels and liver productions of myeloperoxidase and reactive oxygen species, the markers of tissue inflammation and oxidative stress, were increased in untreated db/db mice, which were reduced by dapagliflozin administration. These results demonstrate that dapagliflozin not only improves hyperglycemia but also slows the progression of diabetes-associated glomerulosclerosis and liver fibrosis by improving hyperglycemia-induced tissue inflammation and oxidative stress.
DOI: 10.1152/ajpendo.00086.2017

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S03 Anti-fibrosis fibrosis Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 Details
S04 Anti-oxidative stress oxidative stress α-tocopherol: antioxidant Vitamin E Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T02 Sodium/glucose cotransporter 2 SLC5A2 inhibitor Transporter P31639 SC5A2_HUMAN Details
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T07 Bile acid receptor NR1H4 agonist Nuclear hormone receptor Q96RI1 NR1H4_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D549 SGLT2 inhibitor Chemical drug -- SGLT2 inhibitor -- Under clinical trials Details
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D083 CLA Chemical drug DB01211 KCNH2; SLCO1B1; SLCO1B3 -- Under clinical trials Details
D101 Dapagliflozin Chemical drug DB06292 SLC5A2 antagonist; SLC5A2 inhibitor Antidiabetic drug Under clinical trials Details