Research Highlights

­­­­­­­­­ IMMUNITY­ ACUTE INJURY Nephrocytes: a role Uromodulin regulates oxidative stress in immunity A new study reports that the kidney-derived levels and an increase in systemic oxidative uromodulin is a regulator of DNA damage. Furthermore, high levels of Peptidoglycans (PGNs) are pathogen- oxidative stress. Although the majority oxidative DNA damage were associated with associated molecular patterns (PAMPs) that of uromodulin is secreted into the , mortality and need for dialysis in the patients are shed by bacteria, including those of the a small amount is released into the kidney who developed AKI. microbiome, to stimulate an immune response. interstitium and circulation. Finally, the researchers show that Uncontrolled immune stimulation can lead “Our longstanding hypothesis is uromodulin inhibits activation of the to chronic inflammation and shortened that uromodulin is a defender of kidney nonselective calcium ion channel TRPM2, lifespan; hence, mechanisms exist to prevent and systemic homeostasis,” explains which has previously been shown to have excessive immune activation in response researcher Tarek El-Achkar. “Supporting a role in RAC1-dependent signalling and to PAMPs. New research in Drosophila demon- this hypothesis, recent studies have oxidative stress in AKI. They demonstrate strates a role for nephrocytes in this regulatory shown that high levels of circulating that the increase in systemic oxidative process. “We show that nephrocytes remove uromodulin are associated with reduced stress that is induced by uromodulin microbiota-derived PGN fragments from the mortality and reduced risk of chronic deficiency is TRPM2-dependent. circulation to prevent aberrant immune activa- kidney disease (CKD) and acute kidney “Regulation of oxidative stress could tion,” explains Nicolas Buchon. “Thus, renal injury (AKI).” explain the link between serum uromodulin filtration of microbiota-derived PGN maintains To investigate the molecular signals levels and systemic outcomes,” says El-Achkar. immune homeostasis in Drosophila.” that are regulated by uromodulin in kidney “If our findings are validated in large human Drosophila nephrocytes have molecular and cells, El-Achkar and colleagues used studies, we envision future therapeutic functional similarities to podocytes and to cells unbiased omics approaches. They show that strategies that aim to increase the levels of the reticuloendothelial system. To assess the uromodulin inhibits RAC1–JNK activation of systemic uromodulin in specific clinical role of nephrocytes and haemo­lymph (insect in proximal tubule cells and that uromodulin situations characterized by profound blood) filtration in immunity, Buchon and col- deficiency leads to increased systemic and uromodulin deficiency.” leagues studied Drosophila with a mutation in renal oxidative stress. Ellen F. Carney Klf15 — the ortholog of human KLF15, which is In a mouse model and in patients Original article LaFavers, K. A. et al. Circulating required for podocyte differentiation — which undergoing liver transplantation, AKI uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel. Sci. Transl Med. 11, eaaw3639 (2019) lack nephrocytes. Despite the known ability of resulted in a reduction in serum uromodulin nephrocytes to detoxify hemolymph, Buchon and colleagues found that Klf15-null flies were more resistant to infection than wild-type flies. RENAL CELL CARCINOMA Further analyses showed that nephrocytes of wild-type flies removed PGN from the circula- tion via endocytosis and subsequent lyso­somal Synthetic lethality between loss of degradation. This process was impaired in Klf15-null flies, resulting in excess PGN CDK4/6 activity and VHL inactivation in haemolymph and constitutive activation Nearly all cases of clear cell renal cell carcinoma to specifically target tumour cells. To identify of the Toll pathway. Despite their resis­tance to (ccRCC) are associated with inactivating targets with synthetic lethal relationships infection, Klf15-null flies had shorter lifespans mutations or hypermethylation of the with VHL loss, Nicholson and colleagues than wild-type flies. This ­difference was, von Hippel–Lindau tumour suppressor performed synthetic lethal screens in Drosophila however, abolished by raising the flies under VHL. The resultant dysfunctional pVHL leads cells using RNA interference and human germ-free conditions, suggesting that the to accumulation of hypoxia-inducible factor ccRCC cells using a library of chemicals with shortened lifespan of conventionally housed 2α (HIF2α), which activates proliferative and known anticancer activity. These screens led to Klf15-null flies resulted from an aberrant angiogenic pathways. Although small-molecule the identification of CDK4/6 as being synthetic immune response to microbiota. inhibitors of HIF2α have shown some promise lethal with loss of VHL. This synthetic lethal The researchers propose that renal or for the treatment of ccRCC, the response can relationship was independent of HIF2α; reticuloendothelial systems could have similar be variable. The identification of synthetic thus, the antiproliferative effects of CDK4/6 immunoregulatory functions in mammals. lethality between decreased activity of cyclin- inhibition were synergistic with HIF2α inhibi­tion “Renal filtration could regulate the levels of dependent kinases 4 and 6 (CDK4/6) and VHL in VHL-defective ccRCC cells that were microbiota-derived PAMPs, such as PGN, in the inactivation in human and Drosophila ccRCC HIF2α dependent, while still attenuating blood, to maintain immune homeostasis,” says cell lines suggests that the addition of a proliferation of VHL-defective ccRCC cells Buchon. “Thus impairment of renal function CDK4/6 inhibitor to a HIF2α inhibitor might that were HIF2α independent. CDK4/6 could directly induce chronic immune improve outcomes for patients with ccRCC. inhibition also inhibited the growth of ccRCC activation with proinflammatory effects.” Synthetic lethality occurs when a deficiency orthotopic xenografts in mice regardless of in one gene is tolerated, whereas a combination HIF2α dependency. Susan J. Allison of deficiencies in leads to cell death. Susan J. Allison Original article Troha, K. et al. Nephrocytes remove The identification of targets that have synthetic Original article Nicholson, H. E. et al. HIF-independent microbiota-derived peptidoglycan from systemic circulation lethal relationships with genes that are mutated synthetic lethality between CDK4/6 inhibition and VHL loss to maintain immune homeostasis. Immunity https://doi.org/ across species. Sci. Signal. 12, eaay0482 (2019) 10.1016/j.immuni.2019.08.020 (2019) in cancer is an appealing therapeutic approach

2 | JANUARY 2020 | volume 16 www.nature.com/nrneph