eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Yuen, Darren A.; Stead, Bailey E.; Zhang, Yanling; White, Kathryn; Kabir, M. Golam; Thai, Kerri; Advani, Suzanne L.; Connelly, Kim A.; Takano, Tomoko; Zhu, Lei; Cox, Alison; Kelly, Darren J.; Gibson, Ian W.; Takahashi, Takamune; Harris, Raymond C.; Advani, Andrew

doi:10.1681/asn.2011121170

Cited by 123 publications

(127 citation statements)

References 61 publications

(66 reference statements)

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“…27 Podocyte nephrin disintegration in the slit diaphragm has been observed to contribute to loss of protein filtration capacity resulting in excessive urinary protein excretion. 1 However, post-translational acetylation events underlying diabetes-induced loss of podocyte integrity have not yet been elucidated. In this study, we demonstrated that hyperglycemia-induced deacetylation and ubiquitination reactions on the podocyte microstructure deteriorated podocyte homeostasis and renal function in diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Lin

Lee

Hsu

et al. 2014

Journal of the American Society of Nephrology

156

152

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Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemiainduced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Lin

Lee

Hsu

et al. 2014

Journal of the American Society of Nephrology

156

152

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“…Only mice with a blood glucose .15 mmol/L were considered diabetic. At the end of the study period, systolic blood pressure (SBP) was measured using a CODA noninvasive blood pressure system (Kent Scientific, Torrington, CT) (24). Urine albumin excretion was measured by ELISA after metabolic caging for 24 h. None of the mice in studies one, two, or three received supplemental insulin.…”

Section: Study Threementioning

confidence: 99%

“…Podocytes were treated with vehicle or 10 mmol/L MRE-269 for 1 h, fixed in 4% paraformaldehyde, and permeabilized with 0.1% Triton X-100 before staining with 25 mg/mL Alexa Fluor 488 phalloidin (Thermo Scientific) (24). Images were obtained using an Olympus BX60 fluorescence microscope, and staining intensity was determined in 50 cells for each treatment using Adobe Photoshop CS6 (27).…”

Section: Phalloidin Stainingmentioning

confidence: 99%

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

et al. 2016

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Discovery of common pathways that mediate both pancreatic b-cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I 2 (IP) receptor in pancreatic b-cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 39,59-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 b-cells. Its prodrug form, selexipag, augmented GSIS and preserved islet b-cell mass in diabetic mice. Determining that this preservation of b-cell function is mediated through cAMP/protein kinase A (PKA)/ nephrin-dependent pathways, we found that PKA inhibition, nephrin knockdown, or targeted mutation of phosphorylated nephrin tyrosine residues 1176 and 1193 abrogated the actions of MRE-269 in MIN6 cells. Because nephrin is important to glomerular permselectivity, we next set out to determine whether IP receptor agonism similarly affects nephrin phosphorylation in podocytes. Expression of the IP receptor in podocytes was confirmed in cultured cells by immunoblotting and quantitative real-time PCR and in mouse kidneys by immunogold electron microscopy, and its agonism 1) increased cAMP, 2) activated PKA, 3) phosphorylated nephrin, and 4) attenuated albumin transcytosis. Finally, treatment of diabetic endothelial nitric oxide synthase knockout mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria development independently of glucose change. Collectively, these observations describe a pharmacological strategy that posttranslationally modifies nephrin and the effects of this strategy in the pancreas and in the kidney.

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“…18 Consistent with our findings, the previous study suggests that eNOS could be a key mediator of glomerular endothelial cellsepodocytes cross talk. 37 However, the precise mechanism(s) mediating this cross talk will be the focus of future studies. Interestingly, KO-UNX mice developed more mesangial expansion as compared to the other groups, suggesting a potential cross talk between glomerular endothelial cells and mesangial cells as well.…”

Section: Protective Role Of Klf2 In Ckdmentioning

confidence: 99%

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

Zhong

Mallipattu

Estrada

et al. 2016

The American Journal of Pathology

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Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-like factor 2 (KLF2), a shear-stresseinducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cellespecific Klf2 heterozygous knockout mice (KO) and their wild-type littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas KO-UNX mice did not. KO-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of KO-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in KO-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy.

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eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Cited by 123 publications

References 61 publications

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

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