Gains in understanding of podocyte loss

AbstractPodocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.

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Sequential signaling cascade of IL-6 and PGC-1α is involved in high glucose-induced podocyte loss and growth arrest

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2013.05.046 ◽

2013 ◽

Vol 435 (4) ◽

pp. 702-707 ◽

Cited By ~ 18

Author(s):

Dong Il Kim ◽

Soo Hyun Park

Keyword(s):

High Glucose ◽

Growth Arrest ◽

Signaling Cascade ◽

Podocyte Loss

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Pathogenesis of proteinuria in minimal change disease and focal segmental glomerulosclerosis

10.1093/med/9780199592548.003.0059_update_001 ◽

2018 ◽

Author(s):

Patrick Niaudet ◽

Alain Meyrier

Keyword(s):

Serum Albumin ◽

Focal Segmental Glomerulosclerosis ◽

Minimal Change Disease ◽

Minimal Change ◽

Slit Diaphragm ◽

Segmental Glomerulosclerosis ◽

Podocyte Loss ◽

Glomerular Filtrate

It is now well established that the podocyte, and in particular the slit diaphragm structure, are critical to the barrier to serum albumin entering glomerular filtrate in large quantities. In minimal change disease there is proteinuria without podocyte death, whereas in focal segmental glomerulosclerosis there is not only podocyte dysfunction but also podocyte loss.

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Mechanisms of progression of chronic kidney disease

10.1093/med/9780199592548.003.0136 ◽

2015 ◽

Author(s):

Neil Turner

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Lower Risk ◽

Progressive Disease ◽

Serum Proteins ◽

Direct Effects ◽

Therapeutic Approaches ◽

Podocyte Loss ◽

Repair Mechanisms

Three major hypotheses attempt to explain progressive kidney disease following diverse diseases and injuries. To varying degrees they can explain the observed risk factors for progression and the ability of interventions to lower risk. The hyperfiltration hypothesis argues that progression is due to stress on residual nephrons leading to injury and damage to remaining glomeruli. The toxicity of proteinuria hypothesis proposes that serum proteins or bound substances are toxic to tubular or tubulointerstitial cells. This sets up cycles of damage which lead to tubulointerstitial scarring. The podocyte loss hypothesis contends that proteinuria is simply a biomarker for damaged or dying podocytes, and that it is further podocyte loss that leads to progressive glomerulosclerosis. Renoprotective strategies might have direct effects on podocytes. Importantly these different hypotheses suggest different therapeutic approaches to protecting the function of damaged kidneys. Differences between repair mechanisms may explain why some injuries lead to recovery and others to progressive disease, and may suggest new targets for protective therapy.

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Effects of mycophenolate mofetil, valsartan and their combined therapy on preventing podocyte loss in early stage of diabetic nephropathy in rats

Chinese Medical Journal ◽

10.1097/00029330-200706010-00009 ◽

2007 ◽

Vol 120 (11) ◽

pp. 988-995 ◽

Cited By ~ 25

Author(s):

Yan ZHANG ◽

Bing CHEN ◽

Xiang-hua HOU ◽

Guang-ju GUAN ◽

Gang LIU ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Mycophenolate Mofetil ◽

Early Stage ◽

Combined Therapy ◽

Podocyte Loss

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Human podocyte depletion in association with older age and hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00497.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. F656-F668 ◽

Cited By ~ 22

Author(s):

Victor G. Puelles ◽

Luise A. Cullen-McEwen ◽

Georgina E. Taylor ◽

Jinhua Li ◽

Michael D. Hughson ◽

...

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

Kidney Diseases ◽

Demographic Data ◽

Older Age ◽

Glomerular Hypertrophy ◽

Caucasian American ◽

White American ◽

Podocyte Loss ◽

Inner Cortex

Podocyte depletion plays a major role in the development and progression of glomerulosclerosis. Many kidney diseases are more common in older age and often coexist with hypertension. We hypothesized that podocyte depletion develops in association with older age and is exacerbated by hypertension. Kidneys from 19 adult Caucasian American males without overt renal disease were collected at autopsy in Mississippi. Demographic data were obtained from medical and autopsy records. Subjects were categorized by age and hypertension as potential independent and additive contributors to podocyte depletion. Design-based stereology was used to estimate individual glomerular volume and total podocyte number per glomerulus, which allowed the calculation of podocyte density (number per volume). Podocyte depletion was defined as a reduction in podocyte number (absolute depletion) or podocyte density (relative depletion). The cortical location of glomeruli (outer or inner cortex) and presence of parietal podocytes were also recorded. Older age was an independent contributor to both absolute and relative podocyte depletion, featuring glomerular hypertrophy, podocyte loss, and thus reduced podocyte density. Hypertension was an independent contributor to relative podocyte depletion by exacerbating glomerular hypertrophy, mostly in glomeruli from the inner cortex. However, hypertension was not associated with podocyte loss. Absolute and relative podocyte depletion were exacerbated by the combination of older age and hypertension. The proportion of glomeruli with parietal podocytes increased with age but not with hypertension alone. These findings demonstrate that older age and hypertension are independent and additive contributors to podocyte depletion in white American men without kidney disease.

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Renal Podocyte Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin

Experimental Diabetes Research ◽

10.1155/2012/210821 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 43

Author(s):

Junghyun Kim ◽

Eunjin Shon ◽

Chan-Sik Kim ◽

Jin Sook Kim

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Glycated Haemoglobin ◽

Protective Effects ◽

Podocyte Injury ◽

Podocyte Loss ◽

Renal Changes ◽

Hypoglycemic Drug ◽

Antioxidant Effects

Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350 mg/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury.

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Urinary excretion of viable podocytes in health and renal disease

AJP Renal Physiology ◽

10.1152/ajprenal.00404.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. F40-F48 ◽

Cited By ~ 200

Author(s):

Stefanie U. Vogelmann ◽

W. James Nelson ◽

Bryan D. Myers ◽

Kevin V. Lemley

Keyword(s):

Cultured Cells ◽

Growth Behavior ◽

Glomerular Disease ◽

Glomerular Sclerosis ◽

Tunel Staining ◽

Healthy Controls ◽

Podocyte Loss ◽

The Difference ◽

Glomerular Tuft ◽

Quiescent Disease

The loss of glomerular visceral epithelial cells (podocytes) has been associated with the development of glomerular sclerosis and loss of renal function. Viability of podocytes recovered from urine of subjects with glomerular disease and of healthy controls was investigated by propidium iodide exclusion and TUNEL staining. Podocyte loss was quantified by cytospin. The growth behavior in culture of urinary cells and their expression of specific markers were examined. The majority of urinary podocytes are viable, although apoptosis occurs in about one-half of the cells. Patients with active glomerular disease excreted up to 388 podocytes/mg creatinine, whereas healthy controls and patients with quiescent disease generally excreted <0.5 podocytes/mg creatinine. The identity of cultured cells was confirmed by their morphology, growth behavior, and expression of podocyte-specific markers. The difference in growth behavior between healthy controls and subjects with active glomerular disease suggests that in active disease viable podocytes detach from the glomerular tuft due to local environmental factors rather than defects in the podocytes per se, whereas in healthy individuals mostly senescent podocytes are shed.

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