Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice

Ishizaka, Masahiro; Gohda, Tomohito; Takagi, Miyuki; Omote, Keisuke; Sonoda, Yukihiko; Trejo, Juan Alejandro Oliva; Asao, Rin; Hidaka, Teruo; Asanuma, Katsuhiko; Horikoshi, Satoshi; Tomino, Yasuhiko

doi:10.1016/j.bbrc.2015.09.158

Cited by 18 publications

(9 citation statements)

References 26 publications

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“…It is known previously that podocyte-specific deletion of Rac1 in mice, a protein activated by ELMO1 and Dock180 interaction, causes foot process effacement of these cells; but only leads to loss of podocytes under hyperglycaemic conditions22. Since ELMO1, the upstream regulator of Rac1, is associated with endothelial cell protection against apoptosis and with pathogenesis of DN, we predicted that ELMO1 plays the same survival role in the renal system subjected to physiological and hyperglycaemic conditions.…”

Section: Discussionmentioning

confidence: 92%

ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions

Sharma

Heckler

Stoll

et al. 2016

Sci Rep

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Engulfment and cell motility 1 (ELMO1) functions as a guanine exchange factor for Rac1 and was recently found to protect endothelial cells from apoptosis. Genome wide association studies suggest that polymorphisms within human elmo1 act as a potential contributing factor for the development of diabetic nephropathy. Yet, the function of ELMO1 with respect to the glomerulus and how this protein contributes to renal pathology was unknown. Thus, this study aimed to identify the role played by ELMO1 in renal development in zebrafish, under hyperglycaemic conditions, and in diabetic nephropathy patients. In zebrafish, hyperglycaemia did not alter renal ELMO1 expression. However, hyperglycaemia leads to pathophysiological and functional alterations within the pronephros, which could be rescued via ELMO1 overexpression. Zebrafish ELMO1 crispants exhibited a renal pathophysiology due to increased apoptosis which could be rescued by the inhibition of apoptosis. In human samples, immunohistochemical staining of ELMO1 in nondiabetic, diabetic and polycystic kidneys localized ELMO1 in glomerular podocytes and in the tubules. However, ELMO1 was not specifically or distinctly regulated under either one of the disease conditions. Collectively, these results highlight ELMO1 as an important factor for glomerular protection and renal cell survival via decreasing apoptosis, especially under diabetic conditions.

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Section: Discussionmentioning

confidence: 92%

ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions

Sharma

Heckler

Stoll

et al. 2016

Sci Rep

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“…Foot process effacement is evaluated as the proportion of effacement, which is determined as the length of the effacement, to the length of the capillary. We scaled five glomeruli per mouse and five capillaries per glomerulus for three mice in each experimental group using imagej 1.51t software [20]. Glomerular basement membrane (GBM) was also measured using imagej 1.51t software by measured five glomeruli per mouse and three regions of the GBM per glomerulus in three mice in each experimental group.…”

Section: Methodsmentioning

confidence: 99%

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

et al. 2020

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Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta‐Ins2Akita (KK‐Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l‐aspartic acid) levels in diabetic KK‐Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK‐Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK‐Akita mice (DKD group), and (c) treated (double‐volume Asp diet) KK‐Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate‐labeled lectins, wheat germ agglutinin (WGA), and anti‐endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

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“…RhoA/ROCK pathway was the important process in the progression of DN and could induce downstream signaling element cell apoptosis, migration, and differentiation [ 80 ]. Immoderate activities of Rac1, a key element in the Rho GTPases family, could cause macroalbuminuria quickly with focal foot process effacement, indicating podocyte apoptosis and slit diaphragm protein expression reductions in high glucose [ 81 , 82 ]. Wang et al [ 83 ] found that Drp1 at serine 600, as a substrate of Rho signal pathway, not only initiated mitochondrial ROS and podocyte apoptosis in high glucose but also was phosphorylated in ROCK1 knock-out mouse.…”

Section: Main Signaling Pathways Of Podocyte Injury Mechanism In Dmentioning

confidence: 99%

Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy

Dai

Liu

2017

Journal of Diabetes Research

202

139

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Diabetic nephropathy (DN) together with glomerular hyperfiltration has been implicated in the development of diabetic microangiopathy in the initial stage of diabetic diseases. Increased amounts of urinary protein in DN may be associated with functional and morphological alterations of podocyte, mainly including podocyte hypertrophy, epithelial-mesenchymal transdifferentiation (EMT), podocyte detachment, and podocyte apoptosis. Accumulating studies have revealed that disruption in multiple renal signaling pathways had been critical in the progression of these pathological damages, such as adenosine monophosphate-activated kinase signaling pathways (AMPK), wnt/β-catenin signaling pathways, endoplasmic reticulum stress-related signaling pathways, mammalian target of rapamycin (mTOR)/autophagy pathway, and Rho GTPases. In this review, we highlight new molecular insights underlying podocyte injury in the progression of DN, which offer new therapeutic targets to develop important renoprotective treatments for DN over the next decade.

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Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice

Cited by 18 publications

References 26 publications

ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions

ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy

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