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Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

Gangadharan Komala M, Gross S, Mudaliar H, Huang C, Pegg K, Mather A, Shen S, Pollock CA, Panchapakesan U - PLoS ONE (2014)

Bottom Line: Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin.However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

View Article: PubMed Central - PubMed

Affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.

ABSTRACT

Background and objective: Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect.

Research design and methods: We induced diabetes using a low dose streptozotocin protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice).

Results: Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.

Conclusion: Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

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Related in: MedlinePlus

Diabetic mice demonstrated tubular atrophy and tubulointerstitial fibrosis, which was not improved by empagliflozin and partially reduced by telmisartan.Representative photographs of PAS stained sections of tubulointerstitium in A) ctrl, B) ctrl + empa, C) dm, D) dm + empa, E) dm + tel groups and F) Quantification of tubular atrophy in all groups was done by counting the number of atrophic tubules per 400 tubule count (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl). Representative photographs of tubulointerstitial picrosirius red stain in G) ctrl, H) ctrl + empa, I) dm, J) dm + empa, K) dm + tel groups and L) Quantification of tubulointerstitial Sirius red positive collagen content by Image J. Representative photographs of Masson's stain in M) ctrl, N) ctrl + empa, O) dm, P) dm + empa, Q) dm + tel groups and R) Quantification of Masson's positive collagen content by Image J (Magnification  = original X 200). (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl, ** = P<0.001 vs ctrl).
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pone-0108994-g004: Diabetic mice demonstrated tubular atrophy and tubulointerstitial fibrosis, which was not improved by empagliflozin and partially reduced by telmisartan.Representative photographs of PAS stained sections of tubulointerstitium in A) ctrl, B) ctrl + empa, C) dm, D) dm + empa, E) dm + tel groups and F) Quantification of tubular atrophy in all groups was done by counting the number of atrophic tubules per 400 tubule count (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl). Representative photographs of tubulointerstitial picrosirius red stain in G) ctrl, H) ctrl + empa, I) dm, J) dm + empa, K) dm + tel groups and L) Quantification of tubulointerstitial Sirius red positive collagen content by Image J. Representative photographs of Masson's stain in M) ctrl, N) ctrl + empa, O) dm, P) dm + empa, Q) dm + tel groups and R) Quantification of Masson's positive collagen content by Image J (Magnification  = original X 200). (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl, ** = P<0.001 vs ctrl).

Mentions: The diabetic mice (Figure 4C) developed significant tubular atrophy in comparison with control mice (Figure 4A). Empagliflozin did not reduce tubular atrophy (Figure 4D), while temisartan treated diabetic mice showed tubular atrophy not significantly different to control mice (Figure 4E). The degree of interstitial fibrosis was assessed by Sirius Red sensitive collagen staining (Figures 4G-K) and Masson's staining (Figures 4M-Q). The diabetic mice showed a non significant trend towards increased collagen deposition with the sirius red stain. However with the masson's stain, the diabetic mice had significantly increased collagen deposition (Figure 4O), which was not improved by empagliflozin (Figure 4P). Telmisartan treated diabetic mice showed tubulointerstitial fibrosis not significantly different to that of control mice (Figure 4Q).


Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.

Gangadharan Komala M, Gross S, Mudaliar H, Huang C, Pegg K, Mather A, Shen S, Pollock CA, Panchapakesan U - PLoS ONE (2014)

Diabetic mice demonstrated tubular atrophy and tubulointerstitial fibrosis, which was not improved by empagliflozin and partially reduced by telmisartan.Representative photographs of PAS stained sections of tubulointerstitium in A) ctrl, B) ctrl + empa, C) dm, D) dm + empa, E) dm + tel groups and F) Quantification of tubular atrophy in all groups was done by counting the number of atrophic tubules per 400 tubule count (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl). Representative photographs of tubulointerstitial picrosirius red stain in G) ctrl, H) ctrl + empa, I) dm, J) dm + empa, K) dm + tel groups and L) Quantification of tubulointerstitial Sirius red positive collagen content by Image J. Representative photographs of Masson's stain in M) ctrl, N) ctrl + empa, O) dm, P) dm + empa, Q) dm + tel groups and R) Quantification of Masson's positive collagen content by Image J (Magnification  = original X 200). (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl, ** = P<0.001 vs ctrl).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219667&req=5

pone-0108994-g004: Diabetic mice demonstrated tubular atrophy and tubulointerstitial fibrosis, which was not improved by empagliflozin and partially reduced by telmisartan.Representative photographs of PAS stained sections of tubulointerstitium in A) ctrl, B) ctrl + empa, C) dm, D) dm + empa, E) dm + tel groups and F) Quantification of tubular atrophy in all groups was done by counting the number of atrophic tubules per 400 tubule count (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl). Representative photographs of tubulointerstitial picrosirius red stain in G) ctrl, H) ctrl + empa, I) dm, J) dm + empa, K) dm + tel groups and L) Quantification of tubulointerstitial Sirius red positive collagen content by Image J. Representative photographs of Masson's stain in M) ctrl, N) ctrl + empa, O) dm, P) dm + empa, Q) dm + tel groups and R) Quantification of Masson's positive collagen content by Image J (Magnification  = original X 200). (Data are expressed as mean ± SEM with * = P<0.05 vs ctrl, ** = P<0.001 vs ctrl).
Mentions: The diabetic mice (Figure 4C) developed significant tubular atrophy in comparison with control mice (Figure 4A). Empagliflozin did not reduce tubular atrophy (Figure 4D), while temisartan treated diabetic mice showed tubular atrophy not significantly different to control mice (Figure 4E). The degree of interstitial fibrosis was assessed by Sirius Red sensitive collagen staining (Figures 4G-K) and Masson's staining (Figures 4M-Q). The diabetic mice showed a non significant trend towards increased collagen deposition with the sirius red stain. However with the masson's stain, the diabetic mice had significantly increased collagen deposition (Figure 4O), which was not improved by empagliflozin (Figure 4P). Telmisartan treated diabetic mice showed tubulointerstitial fibrosis not significantly different to that of control mice (Figure 4Q).

Bottom Line: Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin.However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

View Article: PubMed Central - PubMed

Affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.

ABSTRACT

Background and objective: Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect.

Research design and methods: We induced diabetes using a low dose streptozotocin protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice).

Results: Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.

Conclusion: Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

Show MeSH
Related in: MedlinePlus