Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats

The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-β1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/−), and homozygous (USF1 −/−) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 −/− diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-β1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 −/− diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-β1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose-induced regulation of USF1.

Section: Discussionsupporting

confidence: 89%

Role of the USF1 transcription factor in diabetic kidney disease

Sanchez

Zhao

You

et al. 2011

“…In contrast to ACE, circulating ACE2 is low to nondetectable in rodents and humans, and tissue sources of the enzyme are more likely to influence the local RAS (12, 40). Diabetic renal injury is generally associated with a reduction in the activity and/or expression of renal tissue ACE2, which may contribute to a deleterious imbalance in the relative expression of ANG II to Ang-(1-7) (21,26,39,52,53,60,63). Genetic deletion of ACE2 or chronic blockade of the enzyme exacerbates diabetic renal injury (47,48,52,60,63).…”

mentioning

confidence: 99%

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Yamaleyeva¹,

Gilliam-Davis

Almeida³

et al. 2012

Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302: F1374 -F1384, 2012. First published February 29, 2012 doi:10.1152/ajprenal.00656.2011We examined the impact of early diabetes on the circulating and kidney renin-angiotensin system (RAS) in male and female mRen2.Lewis (mRen2) hypertensive rats. Diabetes (DB) was induced by streptozotocin (STZ; 65 mg/kg) at 11 wk of age for 4 wk without insulin replacement. Systolic blood pressures were not increased in DB males or females compared with controls (CON). Circulating angiotensinconverting enzyme 2 (ACE2) increased ninefold (P Ͻ 0.05) in DB females and threefold (P Ͻ 0.05) in DB males, but circulating ACE and ANG II were higher in the DB groups. Serum C-reactive protein was elevated in DB females but not DB males, and the vascular responses to acetylcholine and estradiol were attenuated in the DB females. Proteinuria, albuminuria, and angiotensinogen excretion increased to a similar extent in both DB females and males. Glomerular VEGF expression also increased to a similar extent in both DB groups. Renal inflammation (CD68 ϩ cells) increased only in DB females although males exhibited greater inflammation that was not different with DB. Cortical ACE2 did not change in DB females but was reduced (30%) in DB males. Renal neprilysin activity (Ͼ75%, P Ͻ 0.05) was markedly reduced in the DB females to that in the DB and CON males. ACE activity was significantly lower in both female (75%, P Ͻ 0.05) and male (50%; P Ͻ 0.05) DB groups, while cortical ANG II and Ang-(1-7) levels were unchanged. In conclusion, female mRen2 rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite a marked increase in circulating ACE2 and significantly reduced ACE within the kidney.angiotensin; kidney; neprilysin; hypertension; proteinuria ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2), a homolog of ACE, is recognized as an important enzymatic component of the renin-angiotensin system (RAS) that may regulate functional output of this hormonal system (5,7,8,14,28,30,51,50). Although ACE2 was originally characterized for its ability to hydrolyze ANG I to Ang-(1-9), subsequent studies revealed a very high catalytic activity to convert ANG II to Ang-(1-7) (41,44,45,56,58). Indeed, ACE2 inhibition or genetic knockout studies reveal a heightened sensitivity to ANG II-induced increases in blood pressure, as well as an exacerbation of end-organ damage in these experimental models (31,32,46,48,52,60). In contrast to ACE, circulating ACE2 is low to nondetectable in rodents and humans, and tissue sources of the enzyme are more likely to influence the local RAS (12, 40). Diabetic renal injury is generally associated with a reduction in the activity and/or expression of renal tissue ACE2, which may contribute to a deleterious imbalance in the relative expression of ANG I...

“…In the present study it was determined that ACE2 protein levels were similar in LZR and ZDF and that treatment of ZDF with ANG-(1-7) did not modify ACE2 protein levels in the kidney. In line with these observation, Leehey and coworkers found similar glomerular ACE2 levels between LZR and ZDF (31). Furthermore, recently published data showed that female mRen2.Lewis rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite displaying a marked increase in circulating ACE2 and significantly reduced ACE within the kidney (54).…”

Section: Discussionmentioning

confidence: 64%

Angiotensin-(1–7) attenuates diabetic nephropathy in Zucker diabetic fatty rats

Giani

Burghi

Veiras

et al. 2012

Angiotensin (ANG)-(1–7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1–7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1–7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1–7) (100 ng·kg−1·min−1) ( n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1–7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1–7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1–7). Chronic ANG-(1–7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1–7) emerges as a novel target for treatment of diabetic nephropathy.