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

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.