SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy

Abstract

There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. The second aim of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in the progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin, and urinary thiobarbituric acid-reacting substances. SGLT2 inhibition prevented renal lipid accumulation via inhibition of carbohydrate-responsive element-binding protein-β, pyruvate kinase L, SCD-1, and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation and expression of p65, TLR4, MCP-1, and osteopontin. These effects were associated with reduced mesangial expansion, accumulation of the extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice.

Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet‐fed streptozotocin‐treated diabetic rats

“…The present study supports the results of previous studies that demonstrated that DAPA improved the glucose control and levels of C-peptide. [38,39] Moreover, treatment with LPZ significantly decreased the blood glucose and C-peptide levels as compared with the levels in the DC group; these results were in line with those of the previous study [18] that revealed that the glucose-lowering effect of LPZ was a result of increased secretion of gastrin by PPIs. [40] As previously reported, gastrin stimulated β-cell neogenesis and mass expansion.…”

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…Recently, Hosokawa et al showed that Ipragliflozin decreases ectopic lipid accumulation in tubular cells in diabetic mice [238]. In db/db mice, JNJ 39933673, a selective SGLT2i, prevented renal lipid accumulation by inhibition of transcription factor carbohydrate-responsive element-binding protein (ChREBP) β-isoform, a transcription factor that mediates activation of several regulatory enzymes of glycolysis and lipogenesis pathway such as SCD-1 and diacylglycerol O-acyltransferase-1 (DGAT1) [191]. Although further studies are needed overall, it is plausible that, in addition to the well-known effects of SGLT2i (anti-inflammatory, anti-proliferative, and anti-fibrotic), the reduction of tubular lipid deposition could be a new renoprotective mechanism of these molecules [192,239,240].…”

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

“…The effect is enhanced in the setting of hyperglycemia since the latter increases the filtered load of glucose to the proximal tubule, which enhances glucose reabsorption via SGLT2 and as a consequence the glucosuric effect of SGLT2 inhibition. This glucosuric effect may further increase due to a diabetes-associated increase in renal SGLT2 expression, although this remains a matter of debate due to positive and negative data [2–5]. Thus, diabetes increases renal glucose reabsorption via SGLT2, which contributes to maintain hyperglycemia, and SGLT2 inhibition opposes these effects.…”