Renal Disease:Senescence as a new piece of the puzzle

Senescence as a newpiece of the puzzl

Renal Disease: Senescence as a new piece of the puzzle

Senescence as a new piece of the puzzl

Urinary extracellular vesicles and tubular transport

Tubular transport is a key function of the kidney to maintain electrolyte and acid-base homeostasis. Urinary extracellular vesicles (uEVs) harbor water, electrolyte, and acid-base transporters expressed at the apical plasma membrane of tubular epithelial cells. Within the uEV proteome, the correlations between kidney and uEV protein abundances are strongest for tubular transporters. Therefore, uEVs offer a noninvasive approach to probing tubular transport in health and disease. Here, we review how kidney tubular physiology is reflected in uEVs and, conversely, how uEVs may modify tubular transport. Clinically, uEV tubular transporter profiling has been applied to rare diseases, such as inherited tubulopathies, but also to more common conditions, such as hypertension and kidney disease. Although uEVs hold the promise to advance the diagnosis of kidney disease to the molecular level, several biological and technical complexities must still be addressed. The future will tell whether uEV analysis will mainly be a powerful tool to study tubular physiology in humans or whether it will move forward to become a diagnostic bedside test

Validation of a dried blood spot method to measure tacrolimus concentrations in small volumes of mouse blood

Background: The small blood volume of mice complicates tacrolimus pharmacokinetic studies in these animals. Here we explored dried blood spot (DBS) as a novel method to measure tacrolimus blood concentrations in mice. DBS samples were collected from three sampling sites (cheek, tail and heart) and compared with heart whole blood samples measured via LC–MS/MS. Results: Tacrolimus concentrations in the whole blood samples ranged from 2.56 to 27.64 μg/l. DBS of cheek vein blood was the most reliable sampling site, with a mean bias of 0.15 μg/l (95% CI: -4.20 to 4.50). Conclusion: The DBS cheek method can be used for serial monitoring of tacrolimus blood concentrations in mice, offering an animal-friendly method for tacrolimus pharmacokinetic studies in mice

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored