Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice

Abstract

Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

“…Involvement of SHIP2 in glucose metabolism is further supported by a similar short-term AS1949490 treatment, which reduced blood glucose and improved insulin sensitivity in db/db mice (17). In line with previous literature (33, 34), we observed no difference in body weight, albuminuria, or fasting blood glucose in db/db mice after short-term metformin treatment. The latter could be explained by our finding that the renal expression of PCK1 and G6Pase was increased after metformin treatment, apparently enhancing gluconeogenesis in the kidney cortex, compensating for the reduced hepatic glucose production.…”

“…The latter could be explained by our finding that the renal expression of PCK1 and G6Pase was increased after metformin treatment, apparently enhancing gluconeogenesis in the kidney cortex, compensating for the reduced hepatic glucose production. This accords with the role of the kidney in gluconeogenesis (35) and is supported by a previous study revealing that 10 wk metformin treatment of db/db mice exacerbates the diabetes-induced increase in the expression of gluconeogenic genes in the kidney (34). The regulation of gluconeogenesis by metformin is complex (5).…”

Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus

“…Other studies also showed no changes in albuminuria by SGLT2 inhibitors [27,30]. The issue is complicated in that the duration of treatment appears to influence the effects of treatment on albuminuria.…”

Empagliflozin: a new strategy for nephroprotection in diabetes

“…На фоне комбинации эмпаглифло-зина и метформина наблюдалось снижение содержания коллагена IV типа в почках. Однако достоверных разли-чий между группами эмпаглифлозина и плацебо в уровне СКФ, альбуминурии, выраженности фиброза клубочков и интерстиция, а также в уровне экскреции маркеров ту-булоинтерстициального повреждения не найдено [37]. На фоне применения эмпаглифлозина у крыс линии CRHD (модель СД2 и гипертонической болезни) наблю-далось уменьшение выраженности снижения экспрессии нефрина в клубочках и уменьшение протеинурии при снижении уровня гликемии и АД [38].…”