Continuum of historical controversies regarding the structural-functional relationship of the glomerular ultrafiltration unit

Kanwar, Yashpal S.

doi:10.1152/ajprenal.00640.2014

Cited by 10 publications

(4 citation statements)

References 29 publications

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“…47–50 Integrated functions of glomerular endothelial cells and podocytes are essential to maintain normal homeostasis of glomerular capillaries. 51 Podocytes maintain the structure of glomerular endothelial cells via the production of vascular endothelial growth factor (VEGF). 52 Moreover, the structure of glomerular endothelial cells is abnormal in podocyte-specific VEGF-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice

Nagasu

Satoh

Kiyokage

et al. 2016

Laboratory Investigation

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Increased generation of reactive oxygen species (ROS) is a common denominative pathogenic mechanism underlying vascular and renal complications in diabetes mellitus. Endothelial NAD(P)H oxidase is a major source of vascular ROS, and it has an important role in endothelial dysfunction. We hypothesized that activation of endothelial NAD(P)H oxidase initiates and worsens the progression of diabetic nephropathy, particularly in the development of albuminuria. We used transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NAD(P)H oxidase, Nox2 (NOX2TG). NOX2TG mice were crossed with Akita insulin-dependent diabetic (Akita) mice that develop progressive hyperglycemia. We compared the progression of diabetic nephropathy in Akita versus NOX2TG-Akita mice. NOX2TG-Akita mice and Akita mice developed significant albuminuria above the baseline at 6 and 10 weeks of age, respectively. Compared with Akita mice, NOX2TG-Akita mice exhibited higher levels of NAD(P)H oxidase activity in glomeruli, developed glomerular endothelial perturbations, and attenuated expression of glomerular glycocalyx. Moreover, in contrast to Akita mice, the NOX2TG-Akita mice had numerous endothelial microparticles (blebs), as detected by scanning electron microscopy, and increased glomerular permeability. Furthermore, NOX2TG-Akita mice exhibited distinct phenotypic changes in glomerular mesangial cells expressing α-smooth muscle actin, and in podocytes expressing increased levels of desmin, whereas the glomeruli generated increased levels of ROS. In conclusion, activation of endothelial NAD(P)H oxidase in the presence of hyperglycemia initiated and exacerbated diabetic nephropathy characterized by the development of albuminuria. Moreover, ROS generated in the endothelium compounded glomerular dysfunctions by altering the phenotypes of mesangial cells and compromising the integrity of the podocytes.

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Section: Discussionmentioning

confidence: 99%

Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice

Nagasu

Satoh

Kiyokage

et al. 2016

Laboratory Investigation

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“…These essential studies would be necessary pretexts before determining whether inhibition of KIBRA signaling could in the future be part of a targeted therapeutic strategy to treat certain glomerular disorders. Although our focus in this study is on the glomerular podocyte, it is important to keep in mind that normal homeostasis of the glomerular capillary is maintained by the integrated functions of all of its layers, including the endothelium and basement membrane, in addition to the podocyte (46). Given that the main phenotype of KIBRA constitutive KO mice was memory impairment and that no other systemic effects were observed, it is possible that the design of a KIBRA inhibitor drug without the ability to cross the blood-brain barrier in the future could offer potential treatment for glomerular disease and spare patients adverse neurological side effects.…”

Section: Kibra In Podocyte Survivalmentioning

confidence: 99%

The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics

Meliambro¹,

Wong²,

Ray³

et al. 2017

Journal of Biological Chemistry

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Kidney podocytes represent a key constituent of the glomerular filtration barrier. Identifying the molecular mechanisms of podocyte injury and survival is important for better understanding and management of kidney diseases. KIBRA (dney in protein), an upstream regulator of the Hippo signaling pathway encoded by the gene, shares the pro-injury properties of its putative binding partner dendrin and antagonizes the pro-survival signaling of the downstream Hippo pathway effector YAP (Yes-associated protein) in and MCF10A cells. We recently identified YAP as an essential component of the glomerular filtration barrier that promotes podocyte survival by inhibiting dendrin pro-apoptotic function. Despite these recent advances, the signaling pathways that mediate podocyte injury remain poorly understood. Here we tested the hypothesis that, similar to its role in other model systems, KIBRA promotes podocyte injury. We found increased expression of KIBRA and phosphorylated YAP protein in glomeruli of patients with biopsy-proven focal segmental glomerulosclerosis (FSGS). KIBRA/ overexpression in murine podocytes promoted LATS kinase phosphorylation, leading to subsequent YAP Ser-127 phosphorylation, YAP cytoplasmic sequestration, and reduction in YAP target gene expression. Functionally, KIBRA overexpression induced significant morphological changes in podocytes, including disruption of the actin cytoskeletal architecture and reduction of focal adhesion size and number, all of which were rescued by subsequent YAP overexpression. Conversely, constitutive KIBRA knockout mice displayed reduced phosphorylated YAP and increased YAP expression at baseline. These mice were protected from acute podocyte foot process effacement following protamine sulfate perfusion. KIBRA knockdown podocytes were also protected against protamine-induced injury. These findings suggest an important role for KIBRA in the pathogenesis of podocyte injury and the progression of proteinuric kidney disease.

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“…For decades, the GFB had been considered to include both size- and charge-selective components (79, 80). Classic studies using tracers of comparable composition and size, but with varying degrees of positive or negative charge, led to the theory of “charge selectivity.” These studies showed that, with decreasing negative charge, the tracers penetrated into, or across, the GFB to a greater degree (22, 32).…”

Section: The Gbm and Its Role In The Glomerular Filtration Barriermentioning

confidence: 99%

Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?

Marshall

2016

American Journal of Physiology-Renal Physiology

105

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Diabetic nephropathy (DN) is the leading cause of chronic kidney disease in the United States and is a major cause of cardiovascular disease and death. DN develops insidiously over a span of years before clinical manifestations, including microalbuminuria and declining glomerular filtration rate (GFR), are evident. During the clinically silent period, structural lesions develop, including glomerular basement membrane (GBM) thickening, mesangial expansion, and glomerulosclerosis. Once microalbuminuria is clinically apparent, structural lesions are often considerably advanced, and GFR decline may then proceed rapidly toward end-stage kidney disease. Given the current lack of sensitive biomarkers for detecting early DN, a shift in focus toward examining the cellular and molecular basis for the earliest structural change in DN, i.e., GBM thickening, may be warranted. Observed within one to two years following the onset of diabetes, GBM thickening precedes clinically evident albuminuria. In the mature glomerulus, the podocyte is likely key in modifying the GBM, synthesizing and assembling matrix components, both in physiological and pathological states. Podocytes also secrete matrix metalloproteinases, crucial mediators in extracellular matrix turnover. Studies have shown that the critical podocyte-GBM interface is disrupted in the diabetic milieu. Just as healthy podocytes are essential for maintaining the normal GBM structure and function, injured podocytes likely have a fundamental role in upsetting the balance between the GBM’s synthetic and degradative pathways. This article will explore the biological significance of GBM thickening in DN by reviewing what is known about the GBM’s formation, its maintenance during health, and its disruption in DN.

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Continuum of historical controversies regarding the structural-functional relationship of the glomerular ultrafiltration unit

Cited by 10 publications

References 29 publications

Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice

Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice

The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics

Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?

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