Amelioration of Established Diabetic Nephropathy by Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in &lt;i&gt;db/db&lt;/i&gt; Mice

Sugaru, Eiji; Nakagawa, Tsutomu; Ono-Kishino, Michiko; Nagamine, Jun; Tokunaga, Teruhisa; Kitoh, Makoto; Hume, W. Ewan; Nagata, Ryu; Taiji, Mutsuo

doi:10.1159/000097603

Cited by 15 publications

(14 citation statements)

References 65 publications

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“…One hypothesis could therefore be that hyperglycemia enhanced tubular apoptosis by increasing the Bax/Bcl-xL ratio, thus having a pro-poptotic effect. STZ-induced diabetes leads to apoptosis in RPTCs and to a lesser degree in distal tubules, but not in the glomeruli, confirming previous findings of a pro-apoptotic effect of diabetes on RPTCs (36). Treatment with insulin and/or RAS blockers leads to an almost complete absence of apoptosis in kidneys of non Tg and Tg mice.…”

Section: Diabetic Nephropathy 36supporting

confidence: 87%

Renal Angiotensinogen Gene Expression and Tubular Atrophy in Diabetic Nephropathy

Nouthe¹,

Saleh²,

Zhang³

et al. 2012

Diabetic Nephropathy

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Section: Diabetic Nephropathy 36supporting

confidence: 87%

Renal Angiotensinogen Gene Expression and Tubular Atrophy in Diabetic Nephropathy

Nouthe¹,

Saleh²,

Zhang³

et al. 2012

Diabetic Nephropathy

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“…These observations are consistent with previous findings that diabetes induces apoptosis in RPT, but not in glomeruli of db/db mice and STZ-diabetic rats. 28,29 Our results highlight an important role for intrarenal Agt gene expression in mediating tubular apoptosis in the diabetic mouse kidney. Indeed, the numbers of TUNEL-positive RPTC were significantly higher in Tg mice than in non-Tg mice and were effectively reduced after treatment with RAS blockers.…”

Section: Discussionmentioning

confidence: 63%

Overexpression of Angiotensinogen Increases Tubular Apoptosis in Diabetes

Liu

Brezniceanu²,

Wei³

et al. 2008

Journal of the American Society of Nephrology

144

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The intrarenal renin-angiotensin system (RAS) plays an important role in the progression of diabetic nephropathy. We have previously reported that mice overexpressing angiotensinogen in renal proximal tubular cells (RPTC) develop hypertension, albuminuria, and renal injury. Here, we investigated whether activation of the intrarenal RAS contributes to apoptosis of RPTC in diabetes. Induction of diabetes with streptozotocin in these transgenic mice led to significant increases in BP, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared with diabetic nontransgenic littermates. Insulin and/or RAS blockers markedly attenuated these changes. Hydralazine prevented hypertension but not albuminuria, RPTC apoptosis, or proapoptotic gene expression. In vitro, high-glucose medium significantly increased apoptosis and caspase-3 activity in rat immortalized RPTC overexpressing angiotensinogen compared with control cells, and these changes were prevented by insulin and/or RAS blockers. In conclusion, intrarenal RAS activation and high glucose may act in concert to increase tubular apoptosis in diabetes, independent of systemic hypertension. Diabetic nephropathy (DN) is the leading cause of all ESRD in North America, accounting for 45% to 50% of all cases. 1,2 Intensive insulin therapy and chronic treatment with renin-angiotensin system (RAS) blockers are effective in retarding DN progression but do not provide a cure. [3][4][5] The local intrarenal RAS is well accepted. 6,7 Renal proximal tubular cells (RPTC) express all components of the RAS. 8 -10 Angiotensin II (Ang II) levels and RAS genes are elevated in the kidneys of diabetic rats and humans, 11-13 implying an important role for the intrarenal RAS in DN progression.Glomerular changes in DN first consist of hypertrophy and, later, thickening of the glomerular basement membrane, followed by expansion of the mesangial matrix and glomerulosclerosis. 14 -16 However, the gradual decline of renal function in later stages of DN is invariably associated with tubular atrophy and interstitial fibrosis, hallmarks of ESRD. 17,18 In fact, tubular atrophy and interstitial fibrosis are closely associated with loss of renal function and appear to be better predictors of renal disease progression than glomerular pathology. 15-18 Tubular atrophy in DN is incompletely understood, although apoptosis is a candidate mechanism. Indeed, apoptosis has been detected in RPTC of diabetic mouse, rat, and human kidneys. 19 -24

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“…There was no significant difference in body weight between nontransgenic and transgenic mice at 26 wk of age. The albumin excretion in the transgenic mice reached a level 2.4-fold higher than in nontransgenic controls by 26 wk of age, while db/db diabetic mice typically exhibit an earlier and greater increase in albuminuria (44). Although significant GBM thickening was a feature of the GT1S transgenic glomeruli, the change was small, and the combined findings of modest albuminuria and GBM thickening in GT1S mice vs. diabetic mice suggested the glomerular barrier damage of diabetes requires more than excessive glucose uptake and metabolism in mesangial cells.…”

Section: Discussionmentioning

confidence: 85%

Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis

Wang

Heilig

Saunders

et al. 2010

American Journal of Physiology-Renal Physiology

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Previous work identified an important role for hyperglycemia in diabetic nephropathy (The Diabetes Control and Complications Trial Research Group. N Engl J Med 329: 977-986, 1993; UK Prospective Diabetes Study Group. Lancet 352: 837-853, 1998), and increased glomerular GLUT1 has been implicated. However, the roles of GLUT1 and intracellular glucose have not been determined. Here, we developed transgenic GLUT1-overexpressing mice (GT1S) to characterize the roles of GLUT1 and intracellular glucose in the development of glomerular disease without diabetes. GLUT1 was overexpressed in glomerular mesangial cells (MC) of C57BL6 mice, a line relatively resistant to diabetic nephropathy. Blood pressure, blood glucose, glomerular morphometry, matrix proteins, cell signaling, transcription factors, and selected growth factors were examined. Kidneys of GT1S mice overexpressed GLUT1 in glomerular MCs and small vessels, rather than renal tubules. GT1S mice were neither diabetic nor hypertensive. Glomerular GLUT1, glucose uptake, mean capillary diameter, and mean glomerular volume were all increased in the GT1S mice. Moderately severe glomerulosclerosis (GS) was established by 26 wk of age in GT1S mice, with increased glomerular type IV collagen and fibronectin. Modest increases in glomerular basement membrane thickness and albuminuria were detected with podocyte foot processes largely preserved, in the absence of podocyte GLUT1 overexpression. Activation of glomerular PKC, along with increased transforming growth factor-beta1, VEGFR1, VEGFR2, and VEGF were all detected in glomeruli of GT1S mice, likely contributing to GS. The transcription factor NF-kappaB was also activated. Overexpression of glomerular GLUT1, mimicking the diabetic GLUT1 response, produced numerous features typical of diabetic glomerular disease, without diabetes or hypertension. This suggested GLUT1 may play an important role in the development of diabetic GS.

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Amelioration of Established Diabetic Nephropathy by Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in <i>db/db</i> Mice

Cited by 15 publications

References 65 publications

Renal Angiotensinogen Gene Expression and Tubular Atrophy in Diabetic Nephropathy

Renal Angiotensinogen Gene Expression and Tubular Atrophy in Diabetic Nephropathy

Overexpression of Angiotensinogen Increases Tubular Apoptosis in Diabetes

Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis

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