Metabolically active and polyploid renal tissues rely on graded cytoprotection to drive developmental and homeostatic stress resilience

Abstract

Body tissues are frequently exposed to stress, from toxic byproducts generated during cellular metabolism through to infection or wounding. Although it is well-established that tissues respond to exogenous injury by rapidly upregulating cytoprotective machinery, how energetically demanding tissues – vulnerable to persistent endogenous insult – withstand stress is poorly understood. Here, we show that the cytoprotective factors Nrf2 and Gadd45 act within a specific renal cell subtype, the energetically and biosynthetically active ‘principal’ cells, to drive stress resilience during Drosophila renal development and homeostasis. Renal tubules lacking Gadd45 exhibit striking morphogenetic defects (with cell death, inflammatory infiltration and reduced ploidy) and accumulate significant DNA damage in post-embryonic life. In parallel, the transcription factor Nrf2 is active during periods of intense renal physiological activity, where it protects metabolically active renal cells from oxidative damage. Despite its constitutive nature, renal cytoprotective activity must be precisely balanced and sustained at modest sub-injury levels; indeed, further experimental elevation dramatically perturbs renal development and function. We suggest that tissues requiring long-term protection must employ restrained cytoprotective activity, whereas higher levels might only be beneficial if activated transiently pre-emptive to exogenous insult.

Post-treatment With Irisin Attenuates Acute Kidney Injury in Sepsis Mice Through Anti-Ferroptosis via the SIRT1/Nrf2 Pathway

“…The MMP of HK-2 cells was measured by using the JC-1 fluorescent probe (CAS 3520-43-2, Abcam), according to the instructions of the manufacturer ( Burbridge et al, 2021 ). Cells were treated with 5 μM JC-1 in the dark for 30 min at 37°C.…”

A PI3K-calcium-Nox axis primes leukocyte Nrf2 to boost immune resilience and limit collateral damage

“…Tissues are constantly exposed to highly reactive and potentially toxic metabolites, such as reactive oxygen species (ROS) derived from cellular metabolism and physiology, or generated upon exposure to radiation or noxious chemicals ( Finkel and Holbrook, 2000 ). Given the uncontrolled accumulation of cellular damage (including oxidative damage to cellular biomolecules) is considered to be a leading cause of tissue damage and aging ( Gladyshev, 2014 ; Liochev, 2013 ), cells must employ powerful cytoprotective strategies to mitigate indiscriminate, deleterious effects of ROS (and other toxic byproducts) and shield tissues from potential injury ( Bise et al, 2019 ; Burbridge et al, 2021 ; Telorack et al, 2016 ; Weavers et al, 2019 ). Cytoprotective strategies may thus be crucial in vivo to sustain tissue health and delay a progressive decline in tissue function.…”

“…Drosophila has recently emerged as an invaluable in vivo system to explore the pathway(s) conferring “resilience” to oxidative stress, particularly in vulnerable epithelial tissues following injury ( Burbridge et al, 2021 ; Mundorf et al, 2019 ; Weavers et al, 2019 ). Here, we characterize the cytoprotective mechanism(s) that increase Drosophila macrophage tolerance to oxidative stress during immune surveillance and inflammatory migration.…”