FP413THE COMPARATIVE EFFECT OF APX-115, PAN-NOX INHIBITOR, AND ANGIOTENSIN RECEPTOR ANTAGONIST ON DIABETIC NEPHROPATHY IN TYPE 2 DIABETIC MICE

Diabetic patients are often treated with an ACEi (angiotensin-converting enzyme inhibitor) or angiotensin receptor antagonist against hypertension or albuminuria. These drugs also have a positive impact on glucose tolerance, but the mechanism for this remains elusive. Hypothesizing a positive non-additive effect, we studied whether the angiotensin receptor antagonist telmisartan or the ACEi ramipril acutely influence insulin secretion and glycaemia in vivo in healthy and Type 2 diabetic rats through effects on islet blood perfusion. Telmisartan and ramipril were injected intravenously into anaesthetized non-diabetic Wistar rats or Type 2 diabetic GK (Goto–Kakizaki) rats. In non-diabetic Wistar rats, neither whole PBF (pancreatic blood flow) nor IBF (islet blood flow) were significantly influenced by telmisartan and ramipril, alone or in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril when used in combination, whereas ABF (adrenal blood flow) was not affected by any of the drugs. Telmisartan and ramipril both significantly increased serum insulin levels, but did not influence glycaemia. In Type 2 diabetic GK rats, both whole PBF and IBF were significantly decreased by telmisartan and ramipril, but only when used in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril alone, but not when used in combination, whereas ABF was not affected by any of the drugs. Telmisartan and ramipril both significantly decreased serum insulin levels, and non-additively elevated blood glucose levels. In conclusion, the present study suggests that a local pancreatic RAS (renin–angiotensin system), sensitive to acute administration of telmisartan and ramipril, controls pancreatic IBF and insulin secretion and thereby has an impact on glucose tolerance. Our findings indicate unexpected significant differences in the effects of these agents on islet microcirculation, in vivo insulin secretion and glycaemia between healthy and Type 2 diabetic rats.

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Diabetic Nephropathy in Spontaneously Type 2 Diabetic Nonhuman Primates (Rhesus Monkeys Macaca mulatta ): Comparator Validation of Angiotensin Receptor Blocker Valsartan

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.07592 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Barbara Caleen Hansen ◽

Zunyuan Yang ◽

Yinan Liang ◽

Zunwei Yao ◽

Licai Zeng ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Macaca Mulatta ◽

Rhesus Monkeys ◽

Angiotensin Receptor Blocker ◽

Nonhuman Primates ◽

Receptor Blocker ◽

Angiotensin Receptor ◽

Type 2 Diabetic

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Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy

Chinese Medical Journal ◽

10.4103/0366-6999.245277 ◽

2018 ◽

Vol 131 (22) ◽

pp. 2658-2665 ◽

Cited By ~ 4

Author(s):

Dan-Dan Qiu ◽

Jing Liu ◽

Jing-Song Shi ◽

Yu An ◽

Yong-Chun Ge ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Angiotensin Receptor Blockers ◽

Dipeptidyl Peptidase ◽

Angiotensin Receptor ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Receptor Blockers ◽

Type 2 Diabetic

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Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes

AJP Renal Physiology ◽

10.1152/ajprenal.00509.2020 ◽

2021 ◽

Vol 320 (4) ◽

pp. F548-F558

Author(s):

Hyun Soon Lee ◽

Ji Yeon Suh ◽

Byeong-Choel Kang ◽

Eugene Lee

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Fish Oil ◽

Olive Oil ◽

Renal Cortex ◽

Diabetic Mice ◽

Podocyte Injury ◽

Type 2 Diabetic

In podocytes, PA rapidly induced immunoproteasome expression but ultimately decreased it, while OA and EPA restored the decreased immunoproteasome levels. In the renal cortex of type 2 diabetic mice, immunoproteasome expression was significantly decreased, whereas feeding of OA-rich olive oil or EPA-rich fish oil diets protected them against the reduced immunoproteasome expression and progression of diabetic nephropathy. Thus, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression may be related to the pathogenesis of diabetic nephropathy.

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The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00145.2014 ◽

2014 ◽

Vol 307 (3) ◽

pp. F317-F325 ◽

Cited By ~ 114

Author(s):

Florian Gembardt ◽

Christoph Bartaun ◽

Natalia Jarzebska ◽

Eric Mayoux ◽

Vladimir T. Todorov ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Sglt2 Inhibitor ◽

Western World ◽

Diabetic Mice ◽

Antidiabetic Therapy ◽

Beneficial Effects ◽

Stage Renal Disease ◽

Early Features ◽

Type 2 Diabetic

Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na+-glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-Lep<ob>/WiscJ (BTBR ob/ ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ ob mice received 1 μg·kg body wt−1·day−1 ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ ob mice with and without hypertension.

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Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis

AJP Renal Physiology ◽

10.1152/ajprenal.00503.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. F873-F886 ◽

Cited By ~ 39

Author(s):

Daisuke Saito ◽

Yohei Maeshima ◽

Tatsuyo Nasu ◽

Hiroko Yamasaki ◽

Katsuyuki Tanabe ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Therapeutic Efficacy ◽

Transforming Growth Factor ◽

Angiogenesis Inhibitor ◽

Therapeutic Effects ◽

Mrna Levels ◽

Diabetic Mice ◽

Protein Levels ◽

Type 2 Diabetic

The involvement of VEGF-A as well as the therapeutic efficacy of angiogenesis inhibitors in diabetic nephropathy have been reported. We recently reported the therapeutic effects of vasohibin-1 (VASH-1), an endogenous angiogenesis inhibitor, in a type 1 diabetic nephropathy model (Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Diabetes 58: 2365–2375, 2009). In this study, we investigated the therapeutic efficacy of VASH-1 on renal alterations in obese mice with type 2 diabetes. Diabetic db/db mice received intravenous injections of adenoviral vectors encoding human VASH-1 (AdhVASH-1) and were euthanized 8 wk later. AdhVASH-1 treatment resulted in significant suppression of glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase in the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix. An increase in the renal levels of VEGF-A, VEGFR-2, transforming growth factor (TGF)-β1, and monocyte chemoattractant protein-1 in diabetic animals was significantly suppressed by AdhVASH-1 (immunoblotting). AdhVASH-1 treatment significantly recovered the loss and altered the distribution patterns of nephrin and zonula occludens (ZO)-1 and suppressed the increase in the number of fibroblast-specific protein-1 (FSP-1+) and desmin+ podocytes in diabetic mice. In vitro, recombinant human VASH-1 (rhVASH-1) dose dependently suppressed the upregulation of VEGF induced by high ambient glucose (25 mM) in cultured mouse podocytes. In addition, rhVASH-1 significantly recovered the mRNA levels of nephrin and the protein levels of ZO-1 and P-cadherin and suppressed the increase in protein levels of desmin, FSP-1, Snail, and Slug in podocytes under high-glucose condition. Taken together, these results suggest the potential use of VASH-1 as a novel therapeutic agent in type 2 diabetic nephropathy mediated via antiangiogenic effects and maintenance of podocyte phenotype in association with antiproteinuric effects.

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