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A previously uncharacterized Kidney-Associated Membrane Protein (KAMP) is associated with evolutionary adaptation, energy balance and kidney physiology

ABSTRACT: During the evolution of vertebrates, specific molecular innovations ensured adaptations which resulted in the split of different animal groups. Here comparative genomic analysis became a valued instrument to identify genes associated with the divergence of taxa and speciation events. Using this approach, we identified the association of the previously uncharacterized gene (mouse (1700011H14RIK, human C14ORF105/CCDC198), hereby named Kamp (Kidney-associated membrane protein) with the evolutionary split leading to birds and mammals. Furthermore, by comparing single nuclear polymorphisms of modern humans with Neandertals at the locus of Kamp, we identified gene-flow of Kamp from Neandertals into modern humans. Analyzing the expression of Kamp in humans revealed a restriction to the kidney, pancreas, and few other organs. A knockout of this gene in mice resulted in a structurally normal kidney as validated with micro-computed microtomography scans and single-cell transcriptomics, but with higher Albumin levels in the urine lower serum ferritin levels. Further, interactomics screening revealed an interaction between KAMP and ferritin (heavy chain), which was cross-validated by the analysis of co-localization of both proteins in vesicular and plasma membranes. The membranal localization of KAMP appeared regulated by its N-terminal myristoylation site, as KAMP became cytoplasmic in the absence of this specific sequence. Kamp knockout animals demonstrated increased body weight and decreased energy expenditure. This corresponded to Genome-Wide Association Studies of Kamp linked with higher BMI, diabetes-related pathologies, and macular degeneration in humans. Subsequent gain-of-function experiments showed altered proliferative dynamics and accumulation of KAMP during mitosis. Bioinformatics analysis indicated a protective role of KAMP in renal and liver cancer progression, as suggested by an association of KAMP with epithelial-to-mesenchymal transition and altered localization in tumors versus healthy tissue. Altogether, our results revealed several important roles played by KAMP in a vertebrate body, with specific emphasis on metabolite excretion and energy expenditure.

ORGANISM(S): Mus musculus

PROVIDER: GSE206860 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprised of ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, while sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evident by a rise in serum creatinine and cystatin C, and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy post-sepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NFkB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, loss of FtL did not influence sepsis pathogenesis.

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A previously uncharacterized Kidney-Associated Membrane Protein (KAMP) is associated with evolutionary adaptation, energy balance and kidney physiology

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