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Self-organized Kidney Rudiments: Prospects for Better in vitro Nephrotoxicity Assays.

Davies JA - Biomark Insights (2015)

Bottom Line: Kidneys are essential to life but vulnerable to a range of toxicants, including therapeutic drugs and their metabolites.Most toxicants damage kidneys by one of four mechanisms: damage to the membrane and its junctions, oxidative stress and free radical generation, activation of inflammatory processes, and interference with vascular regulation.So far, this has been done only using renogenic stem cells obtained directly from mouse embryos but, in principle, it should be possible to make them from renogenically directed human-induced pluripotent cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.

ABSTRACT
Kidneys are essential to life but vulnerable to a range of toxicants, including therapeutic drugs and their metabolites. Indeed, nephrotoxicity is often a limiting factor in both drug use and drug development. Most toxicants damage kidneys by one of four mechanisms: damage to the membrane and its junctions, oxidative stress and free radical generation, activation of inflammatory processes, and interference with vascular regulation. Traditionally, animal models were used in preclinical screening for nephrotoxicity, but these can be poorly predictive of human reactions. Animal screens have been joined by simple single-cell-type in vitro assays using primary or immortalized human cells, particularly proximal tubule cells as these are especially vulnerable to toxicants. Recent research, aimed mainly at engineering new kidneys for transplant purposes, has resulted in a method for constructing anatomically realistic mini-kidneys from renogenic stem cells. So far, this has been done only using renogenic stem cells obtained directly from mouse embryos but, in principle, it should be possible to make them from renogenically directed human-induced pluripotent cells. If this can be done, the resulting human-based mini-kidneys would be a promising system for detecting some types of nephrotoxicity and for developing nephroprotective drugs.

No MeSH data available.


Related in: MedlinePlus

Common mechanisms of damage to cells of the renal tubules and interstitium, together with examples of the toxicants that drive each type of damage. This diagram shows three of the four mechanisms described in the text: not shown, because of the scale of the diagram, is interference with vascular function, as caused by NSAIDS in patients with existing circulatory or renal problems.
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f1-bmi-suppl.1-2015-117: Common mechanisms of damage to cells of the renal tubules and interstitium, together with examples of the toxicants that drive each type of damage. This diagram shows three of the four mechanisms described in the text: not shown, because of the scale of the diagram, is interference with vascular function, as caused by NSAIDS in patients with existing circulatory or renal problems.

Mentions: The vulnerability of kidneys to nephrotoxicants is focused mainly (but not exclusively) in three areas. These are (i) the podocytes of the glomerulus, which make the finest element of the glomerular filter through which water and small solutes pass from blood to urine; (ii) the cells of the proximal tubule of the nephron, which recover many “wanted” solutes from the urine and also actively export organic anions and cations; and (iii) the renal interstitium. Fortunately, while the number of different nephrotoxicants is large, most seem to act via a relatively small number of damage pathways (Fig. 1).


Self-organized Kidney Rudiments: Prospects for Better in vitro Nephrotoxicity Assays.

Davies JA - Biomark Insights (2015)

Common mechanisms of damage to cells of the renal tubules and interstitium, together with examples of the toxicants that drive each type of damage. This diagram shows three of the four mechanisms described in the text: not shown, because of the scale of the diagram, is interference with vascular function, as caused by NSAIDS in patients with existing circulatory or renal problems.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4507472&req=5

f1-bmi-suppl.1-2015-117: Common mechanisms of damage to cells of the renal tubules and interstitium, together with examples of the toxicants that drive each type of damage. This diagram shows three of the four mechanisms described in the text: not shown, because of the scale of the diagram, is interference with vascular function, as caused by NSAIDS in patients with existing circulatory or renal problems.
Mentions: The vulnerability of kidneys to nephrotoxicants is focused mainly (but not exclusively) in three areas. These are (i) the podocytes of the glomerulus, which make the finest element of the glomerular filter through which water and small solutes pass from blood to urine; (ii) the cells of the proximal tubule of the nephron, which recover many “wanted” solutes from the urine and also actively export organic anions and cations; and (iii) the renal interstitium. Fortunately, while the number of different nephrotoxicants is large, most seem to act via a relatively small number of damage pathways (Fig. 1).

Bottom Line: Kidneys are essential to life but vulnerable to a range of toxicants, including therapeutic drugs and their metabolites.Most toxicants damage kidneys by one of four mechanisms: damage to the membrane and its junctions, oxidative stress and free radical generation, activation of inflammatory processes, and interference with vascular regulation.So far, this has been done only using renogenic stem cells obtained directly from mouse embryos but, in principle, it should be possible to make them from renogenically directed human-induced pluripotent cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.

ABSTRACT
Kidneys are essential to life but vulnerable to a range of toxicants, including therapeutic drugs and their metabolites. Indeed, nephrotoxicity is often a limiting factor in both drug use and drug development. Most toxicants damage kidneys by one of four mechanisms: damage to the membrane and its junctions, oxidative stress and free radical generation, activation of inflammatory processes, and interference with vascular regulation. Traditionally, animal models were used in preclinical screening for nephrotoxicity, but these can be poorly predictive of human reactions. Animal screens have been joined by simple single-cell-type in vitro assays using primary or immortalized human cells, particularly proximal tubule cells as these are especially vulnerable to toxicants. Recent research, aimed mainly at engineering new kidneys for transplant purposes, has resulted in a method for constructing anatomically realistic mini-kidneys from renogenic stem cells. So far, this has been done only using renogenic stem cells obtained directly from mouse embryos but, in principle, it should be possible to make them from renogenically directed human-induced pluripotent cells. If this can be done, the resulting human-based mini-kidneys would be a promising system for detecting some types of nephrotoxicity and for developing nephroprotective drugs.

No MeSH data available.


Related in: MedlinePlus