Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high‐fat diet

Abstract

Aims/IntroductionComplete mechanisms of renoprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors have not been elucidated yet. Mitochondrial biogenesis is regulated by membrane GTPases, such as optic atrophy factor 1 and mitofusion 2. Here, we investigated whether SGLT2 inhibition in mice fed with a high‐fat diet (HFD) improved mitochondrial morphology and restored mitochondrial biogenesis‐related molecules.Materials and MethodsMice were fed a control diet or HFD with or without ipragliflozin treatment. After 16 weeks, the kidneys were taken out and utilized for the analysis.Results HFD‐fed mice treated with ipragliflozin showed increased caloric intake and ate more food than the control HFD‐fed mice. Body and kidney weights, and blood glucose levels were not altered by ipragliflozin treatment in HFD‐fed mice. Histological analysis showed that, compared with control mice, HFD‐fed mice displayed tubular vacuolation, dilatation and epithelial cell detachment; ipragliflozin ameliorated these alterations. Furthermore, ultrastructural analysis showed that the tubule mitochondria of HFD‐fed mice exhibited significant damage. Again, ipragliflozin reversed the damage to a normal state, and restored optic atrophy factor 1 and mitofusion 2 levels in HFD‐fed mice. Increased urine 8‐hydroxydeoxyguanosine levels in HFD‐fed mice were suppressed by ipragliflozin as well. In vitro experiments using HK‐2 cells revealed that either high glucose or high palmitate suppressed optic atrophy factor 1 and mitofusion 2 levels. Suppression of SGLT2 by a specific small interfering ribonucleic acid or ipragliflozin restored these GTPase levels to their normal values.Conclusions SGLT2 inhibition might act directly on tubular cells and protect kidney tubular cells from mitochondrial damage by metabolic insults regardless of blood glucose levels or improvement in bodyweight reduction.

Inhibition of sodium‐glucose cotransporter 2 ameliorates renal injury in a novel medaka model of nonalcoholic steatohepatitis‐related kidney disease

“…HFD-fed medaka exhibited enlarged glomeruli, dilated glomerular capillaries, and expanded mesangium, changes comparable to changes observed in humans with metabolic syndrome-related glomerulopathy [26]. To date, only a few studies demonstrated the beneficial effect of SGLT2Is on chronic renal injury in NASH animal models and elucidated the underlying mechanisms [27][28][29][30][31]. The mechanisms include the renal inflammation, fibrosis, ER stress, apoptosis and lipid accumulation due to the increased renal expression of reactive oxygen species related to oxidative stress [11,28] and TGF-b1, type IV collagen, and fibronectin [11].…”

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

“…The favourable effects of SGLT2 inhibitors leading to its renoprotective effect have been hypothesized to be caused as a result of diminution of intraglomerular pressure, modifications in local and systemic degree of activation of RAAS, and the aforementioned use of more efficient energy substrates (ketone bodies) . SGLT2 inhibitors have also been to found to protect renal tubular cells by protecting them from mitochondrial damage caused because of metabolic stresses, thereby revealing a novel mechanism of action . Moreover, as far as diabetic and non‐diabetic proteinuric renal diseases are concerned, angiotensin converting enzyme (ACE) inhibitors are the most effective and commonly prescribed drugs, however, it has been proposed that concomitant therapy with SGLT2 inhibitors can be used in those patients in which there is insufficient nephroprotection because of partial blockade of renin‐angiotensin system by ACE inhibitors .…”

“…42 SGLT2 inhibitors have also been to found to protect renal tubular cells by protecting them from mitochondrial damage caused because of metabolic stresses, thereby revealing a novel mechanism of action. 43 Moreover, as far as diabetic and non-diabetic proteinuric renal diseases are concerned, angiotensin converting enzyme (ACE) inhibitors are the most effective and commonly prescribed drugs, however, it has been proposed that concomitant therapy with SGLT2 inhibitors can be used in those patients in which there is insufficient nephroprotection because of partial blockade of renin-angiotensin system by ACE inhibitors. 44 Hence, the favourable effects of SGLT2 inhibitors on the renal system make them the drugs of choice in patients with (and possibly without) diabetes-associated renal impairment.…”

Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes

“…Improving mitochondrial homeostasis and function has the potential to restore renal function. Experimental studies have suggested improvements in mitochondrial damage from SGLT2 inhibition . In the context of these previous studies, we assessed the effects of the SGLT2 inhibitor dapagliflozin on a pre‐specified panel of 13 urinary metabolites known to reflect mitochondrial function in people with diabetes and elevated albuminuria, in order to further understand the possible renoprotective mechanisms of SGLT2 inhibition.…”