Deletion of the gene for adiponectin accelerates diabetic nephropathy in the Ins2 +/C96Y mouse

Fang, Fei; Bae, Eun-Hui; Hu, Amanda; Liu, George C.; Zhou, Xiao‐Hua; Williams, Vanessa; Maksimowski, Nicholas; Lu, Catherine; Konvalinka, Ana; Scholey, James W.

doi:10.1007/s00125-015-3605-9

Cited by 31 publications

(27 citation statements)

References 48 publications

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“…In concordance, Costa et al [32] reported a greater UAE increase in STZ diabetic male rats compared with females. In addition, the presence of hyperfiltration, glomerular hypertrophy, and mesangial matrix expansion has been consistently reported when studying STZ and Akita mice with T1DM [19,20,[44][45][46][47][48]. These observations strengthen the idea that male sex contributes to more severe alterations on glomerular function and morphology in T1DM.…”

Section: Discussionsupporting

confidence: 65%

Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy

Clotet-Freixas

Soler

Palau

et al. 2018

Laboratory Investigation

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Angiotensin-converting enzyme (ACE) and ACE2 play a critical role in the renin-angiotensin system (RAS) by altering angiotensin II (ANGII) levels, thus governing its deleterious effects. Both enzymes are altered by sex and diabetes, and play an important role in the development of diabetic nephropathy (DN). Importantly, previous evidence in diabetic and ACE2-deficient (ACE2KO) males suggest a sex-dependent crosstalk between renal ACE and ACE2. In the present work, we aimed to study the sex-specific susceptibility to diabetes and direct infusion of ANGII in kidney disease progression, with a special focus on its link to ACE2 and ACE. In our mouse model, ANGII promoted hypertension, albuminuria, reduced glomerular filtration, and glomerular histological alterations. ANGII adverse effects were accentuated by diabetes and ACE2 deficiency, in a sex-dependent fashion: ACE2 deficiency accentuated ANGII-induced hypertension, albuminuria, and glomerular hypertrophy in diabetic females, whereas in diabetic males exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion, and podocyte loss. At the molecular level, ANGII downregulated renal ACE gene and enzymatic activity levels, as well as renin gene expression in ACE2KO mice. Interestingly, male sex and diabetes accentuated this effect. Here we show sex dimorphism in the severity of diabetes- and ANGII-related renal lesions, and demonstrate that ACE2- and ACE-related compensatory mechanisms are sex-specific. Supporting our previous findings, the modulation and ANGII-mediated crosstalk between ACE2 and ACE in DN progression was more evident in males. This work increases the understanding of the sex-specific role of ACE2 and ACE in DN, reinforcing the necessity of more personalized treatments targeting RAS.

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Section: Discussionsupporting

confidence: 65%

Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy

Clotet-Freixas

Soler

Palau

et al. 2018

Laboratory Investigation

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“…24,25 Additionally, many studies have reported oxidative stress and inflammation in the kidneys of Akita Ins2+/C96Y C57BL/6 mice, which play an important role in the pathogenesis of diabetic nephropathy. [26][27][28][29][30] However, the genetic background of Akita mutation mice contributes to the severity of albuminuria and histological changes. Gurley et al 31 studied the effect of breeding the Ins2+/C96Y mutation into the DBA/2 and 129/SvEv strains on susceptibility to diabetic nephropathy.…”

Section: Genetic Models Of Type 1 Diabetes In Micementioning

confidence: 99%

Rodent models of diabetic nephropathy: their utility and limitations

Kitada¹,

Ogura²,

Koya³

2016

IJNRD

190

151

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Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic nephropathy.

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“…Over the past two decades, APN has been identified as a potent anti-inflammatory mediator (18)(19)(20)(21)(22) via receptor-dependent mechanisms (23). Various studies indicated that APN is expressed in and acts protectively in renal podocytes (18,24,25), mesangial cells (22,26) and tubular epithelial cells (25,27) in humans and rodents (19,28). It was demonstrated that APN knockout (KO) worsens the severity of kidney structural damage, increases the infiltration of macrophages and upregulates the intrarenal production of proinflammatory factors in subtotal nephrectomized and diabetic mice, whereas the overexpression of APN ameliorated these disorders (22,28).…”

Section: Introductionmentioning

confidence: 99%

“…Various studies indicated that APN is expressed in and acts protectively in renal podocytes (18,24,25), mesangial cells (22,26) and tubular epithelial cells (25,27) in humans and rodents (19,28). It was demonstrated that APN knockout (KO) worsens the severity of kidney structural damage, increases the infiltration of macrophages and upregulates the intrarenal production of proinflammatory factors in subtotal nephrectomized and diabetic mice, whereas the overexpression of APN ameliorated these disorders (22,28). conversely, few studies argued that APN serves as a proinflammatory factor in the renal tubular cell line HK-2 upon stimulation with lipopolysaccharide (LPS) (29) and in acute kidney injury induced by ischemia-reperfusion (30).…”

Section: Introductionmentioning

confidence: 99%

Adiponectin protects against uric acid‑induced renal tubular epithelial inflammatory responses via the AdipoR1/AMPK signaling pathway

Yang

Zhang

et al. 2019

Int J Mol Med

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Adiponectin (APN) exerts anti-inflammatory effects in various cells. Uric acid (UA) induces inflammation in proximal renal tubular epithelial cells (PTEcs). It remains unknown whether APN protects against UA-induced inflammation. In the present study, human PTEcs were incubated with 100 µg/ml soluble (S) UA in the presence or absence of globular (g) APN, APN receptor 1 (AdipoR1)-short hairpin RNA lentivirus or compound c. Reverse transcription-quantitative polymerase chain reaction (RT-qPcR) assays were performed to assess APN mRNA expression. Immunoblotting was used to assess the protein expression of APN, AdipoR1, NAcHT, leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and the activation of tumor necrosis factor (TNF) α and adenosine monophosphate-activated protein kinase (AMPK). ELISA analyses were performed to assess supernatant levels of interleukin (IL)-1β and TNFα. It was observed that SUA significantly enhanced APN mRNA and protein expression (both P<0.05) and increased NLRP3 (P<0.001) and TNFα (P<0.05) protein levels, as well as supernatant levels of IL-1β (P<0.01) and TNFα (P<0.001) compared with untreated cells. gAPN administration significantly limited TNFα synthesis and secretion (both P<0.001), significantly decreased IL-1β release (P<0.01), impacted NLRP3 protein expression and augmented AdipoR1 protein (P<0.01) and AMPK phosphorylation (P<0.05) levels compared with SUA-treated cells. AdipoR1 knockdown significantly promoted the synthesis (P<0.05) and release of TNFα (P<0.001), significantly increased IL-1β supernatant levels (P<0.01) and exhibited little influence on NLRP3 production (P>0.05) compared with the SUA-treated cells. Secreted TNFα levels were significantly increased upon the inhibition of AMPK (P<0.05) and protein levels of IL-1β, NLRP3 and TNFα in cell lysates were not significantly affected (P>0.05). In summary, the data demonstrated that SUA promoted APN expression in PTECs and that gAPN attenuated SUA-induced inflammation through the AdipoR1/AMPK signaling pathway. AdipoR1 knockdown and AMPK inactivation increased SUA-induced inflammatory damage in PTECs. These findings may help to further understand and regulate UA-associated inflammation in proximal renal tubules.

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Deletion of the gene for adiponectin accelerates diabetic nephropathy in the Ins2 +/C96Y mouse

Abstract: Our data suggest that adiponectin is an important determinant of the kidney response to high glucose in vivo and in vitro.

Cited by 31 publications

References 48 publications

Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy

Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy

Rodent models of diabetic nephropathy: their utility and limitations

Adiponectin protects against uric acid‑induced renal tubular epithelial inflammatory responses via the AdipoR1/AMPK signaling pathway

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