Limits...
Sodium glucose transporter ‐ 2 inhibition has no renoprotective effects on non ‐ diabetic chronic kidney disease

View Article: PubMed Central - PubMed

ABSTRACT

Sodium glucose transporter (SGLT)‐2 inhibition has renoprotective effects in diabetic kidney disease. Whether similar effects can be achieved also in non‐diabetic kidney disease is speculative. Chronic kidney disease was induced in C57BL/6N mice by feeding an oxalate‐rich diet for 14 days, known to induce nephrocalcinosis‐related tubular atrophy and interstitial fibrosis without directly affecting the glomerular compartment. Empagliflozin treatment started from day 0 of oxalate feeding had no effect on the decline of glomerular filtration rate, crystal deposition, blood urea nitrogen or serum creatinine levels on day 7 and 14. Tissue morphometry of tubular injury and kidney mRNA levels of kidney injury molecule‐1 or tissue inhibitor of metalloproteinase‐2 were comparable between empagliflozin‐ and vehicle‐treated mice with oxalate nephropathy on day 7 and 14. Similarly, empagliflozin did not affect markers of interstitial fibrosis, including silver, alpha smooth muscle actin (αSMA) and collagen 1 staining, and mRNA levels of fibronectin‐1, collagen 1α1, fibroblast‐specific protein‐1, and transforming growth factor (TGF)‐β2 on day 7 and 14. Thus, the specific renoprotective mechanisms‐of‐action of SGLT2 inhibition in diabetic kidney disease do not apply to chronic oxalosis, a non‐diabetic form of chronic kidney disease.

No MeSH data available.


Related in: MedlinePlus

Empagliflozin has no effect on oxalate nephropathy injury in C57BL/6N mice. C57BL/6N male mice received high‐oxalate diet plus vehicle or high‐oxalate diet with empagliflozin for 7 or 14 days, respectively. (A) PAS staining at various time points and quantification (5× and 20× magnification). Gene expression of the renal injury markers kidney injury molecule 1 (KIM‐1), metallopeptidase inhibitor 2 (TIMP‐2), and insulin like growth factor binding protein 7 (IGFBP7) (B), as well as TNFα and NLRP3 (C) was analyzed using RT‐qPCR at different time points. (D) KIM‐1 immunostaining of kidney sections on day 7 and 14 (20× magnification). Data are mean ± SEM from 10 mice in each group. *P < 0.05, **P < 0.01 and ***P < 0.001 versus control groups. Ns, not significant.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5392518&req=5

phy213228-fig-0003: Empagliflozin has no effect on oxalate nephropathy injury in C57BL/6N mice. C57BL/6N male mice received high‐oxalate diet plus vehicle or high‐oxalate diet with empagliflozin for 7 or 14 days, respectively. (A) PAS staining at various time points and quantification (5× and 20× magnification). Gene expression of the renal injury markers kidney injury molecule 1 (KIM‐1), metallopeptidase inhibitor 2 (TIMP‐2), and insulin like growth factor binding protein 7 (IGFBP7) (B), as well as TNFα and NLRP3 (C) was analyzed using RT‐qPCR at different time points. (D) KIM‐1 immunostaining of kidney sections on day 7 and 14 (20× magnification). Data are mean ± SEM from 10 mice in each group. *P < 0.05, **P < 0.01 and ***P < 0.001 versus control groups. Ns, not significant.

Mentions: Tubular atrophy and interstitial fibrosis are hallmark features of progressive CKD regardless of the underlying disease trigger. We next examined the effect of empagliflozin on renal injury in CaOx crystal‐induced CKD at various time points. Renal CaOx crystal deposition was associated with progressive tubular atrophy in vehicle‐ and empagliflozin‐treated mice after 7 and 14 days compared to control diet, as indicated by PAS staining and tubular injury score (Fig. 3A). Intrarenal mRNA expression of the kidney injury marker KIM‐1, metallopeptidase inhibitor‐2 (TIMP‐2), and insulin like growth factor binding protein 7 (IGFBP7) (Fig. 3B), as well as that of the pro‐inflammatory mediators tumor necrosis factor (TNF)α and the inflammasome protein NLRP3 (Fig. 3C) was increased in oxalate‐fed mice compared to control diet. This was also the case for the protein expression of KIM‐1 in hyperoxaluric mice compared to control diet (Fig. 3D). However, empagliflozin had no renoprotective effect regarding tubular injury and inflammation in CaOx crystal‐induced nephropathy.


Sodium glucose transporter ‐ 2 inhibition has no renoprotective effects on non ‐ diabetic chronic kidney disease
Empagliflozin has no effect on oxalate nephropathy injury in C57BL/6N mice. C57BL/6N male mice received high‐oxalate diet plus vehicle or high‐oxalate diet with empagliflozin for 7 or 14 days, respectively. (A) PAS staining at various time points and quantification (5× and 20× magnification). Gene expression of the renal injury markers kidney injury molecule 1 (KIM‐1), metallopeptidase inhibitor 2 (TIMP‐2), and insulin like growth factor binding protein 7 (IGFBP7) (B), as well as TNFα and NLRP3 (C) was analyzed using RT‐qPCR at different time points. (D) KIM‐1 immunostaining of kidney sections on day 7 and 14 (20× magnification). Data are mean ± SEM from 10 mice in each group. *P < 0.05, **P < 0.01 and ***P < 0.001 versus control groups. Ns, not significant.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392518&req=5

phy213228-fig-0003: Empagliflozin has no effect on oxalate nephropathy injury in C57BL/6N mice. C57BL/6N male mice received high‐oxalate diet plus vehicle or high‐oxalate diet with empagliflozin for 7 or 14 days, respectively. (A) PAS staining at various time points and quantification (5× and 20× magnification). Gene expression of the renal injury markers kidney injury molecule 1 (KIM‐1), metallopeptidase inhibitor 2 (TIMP‐2), and insulin like growth factor binding protein 7 (IGFBP7) (B), as well as TNFα and NLRP3 (C) was analyzed using RT‐qPCR at different time points. (D) KIM‐1 immunostaining of kidney sections on day 7 and 14 (20× magnification). Data are mean ± SEM from 10 mice in each group. *P < 0.05, **P < 0.01 and ***P < 0.001 versus control groups. Ns, not significant.
Mentions: Tubular atrophy and interstitial fibrosis are hallmark features of progressive CKD regardless of the underlying disease trigger. We next examined the effect of empagliflozin on renal injury in CaOx crystal‐induced CKD at various time points. Renal CaOx crystal deposition was associated with progressive tubular atrophy in vehicle‐ and empagliflozin‐treated mice after 7 and 14 days compared to control diet, as indicated by PAS staining and tubular injury score (Fig. 3A). Intrarenal mRNA expression of the kidney injury marker KIM‐1, metallopeptidase inhibitor‐2 (TIMP‐2), and insulin like growth factor binding protein 7 (IGFBP7) (Fig. 3B), as well as that of the pro‐inflammatory mediators tumor necrosis factor (TNF)α and the inflammasome protein NLRP3 (Fig. 3C) was increased in oxalate‐fed mice compared to control diet. This was also the case for the protein expression of KIM‐1 in hyperoxaluric mice compared to control diet (Fig. 3D). However, empagliflozin had no renoprotective effect regarding tubular injury and inflammation in CaOx crystal‐induced nephropathy.

View Article: PubMed Central - PubMed

ABSTRACT

Sodium glucose transporter (SGLT)&#8208;2 inhibition has renoprotective effects in diabetic kidney disease. Whether similar effects can be achieved also in non&#8208;diabetic kidney disease is speculative. Chronic kidney disease was induced in C57BL/6N mice by feeding an oxalate&#8208;rich diet for 14&nbsp;days, known to induce nephrocalcinosis&#8208;related tubular atrophy and interstitial fibrosis without directly affecting the glomerular compartment. Empagliflozin treatment started from day 0 of oxalate feeding had no effect on the decline of glomerular filtration rate, crystal deposition, blood urea nitrogen or serum creatinine levels on day 7 and 14. Tissue morphometry of tubular injury and kidney mRNA levels of kidney injury molecule&#8208;1 or tissue inhibitor of metalloproteinase&#8208;2 were comparable between empagliflozin&#8208; and vehicle&#8208;treated mice with oxalate nephropathy on day 7 and 14. Similarly, empagliflozin did not affect markers of interstitial fibrosis, including silver, alpha smooth muscle actin (&alpha;SMA) and collagen 1 staining, and mRNA levels of fibronectin&#8208;1, collagen 1&alpha;1, fibroblast&#8208;specific protein&#8208;1, and transforming growth factor (TGF)&#8208;&beta;2 on day 7 and 14. Thus, the specific renoprotective mechanisms&#8208;of&#8208;action of SGLT2 inhibition in diabetic kidney disease do not apply to chronic oxalosis, a non&#8208;diabetic form of chronic kidney disease.

No MeSH data available.


Related in: MedlinePlus