There is a growing consensus that men and women differ in their response to kidney injury, and their susceptibility and progression to chronic kidney disease. Similar findings have come from the analysis of different sexes in rodent models. Historically, females have been under-represented in animal modeling and clinical studies. Redressing this imbalance and understanding how sex-related differences in gene expression are generated, and how these influence normal and pathological actions within mammalian organ systems, is a priority. Recent single cell RNA-seq studies in the McMahon group have highlighted extensive sexual dimorphism within proximal tubule segments of the adult mouse kidney. Proximal tubule cells share a major role in chemical modification of circulating metabolites with hepatocytes of the kidney. Proximal tubule cells also have kidney specific actions in resorption, transport and removal of beneficial or harmful molecules. Comparative analysis shows both similar and distinct sexually dimorphic gene sets between the liver and kidney, with potential differences in hormonal interplay (androgens, estrogens, growth hormone) underlying how each organ establishes dimorphic cell states. Pregnancy and nursing present additional demands on the female, specifically. How these demands may impact dimorphic cell states in the female kidney is not clear, even in the mouse model. Due to the absence of comparable, high quality, comparative data for the human kidney, there is no clear idea of the extent of sexual dimorphism in the human kidney, and consequently, which regulatory actions may be shared with mouse models, or are human specific. In this proposal, we will use single nuclear (sn)RNA-seq, snATAC-seq and genetic approaches to determine the regulatory processes establishing sexually dimorphic cell types in the mouse kidney, and those modifying gene activity within proximal tubule cell in the reproductive process. Comparable datasets emerging from worldwide efforts applying single cell technologies to human systems will be co-analyzed for shared and distinct regulatory processes.
Specific Aim 1 will determine regulatory mechanisms, including the action of direct hormone signaling (androgens, estrogen and growth hormone), in generating distinct proximal tubule cell types in the male and female mouse kidney. Kidney datasets will be contrasted with similar data for overlapping gene cohorts within sexually dimorphic hepatocytes.
Specific Aim 2 will determine the regulatory interplay of pregnancy, nursing and prolactin signaling in modifying sexually dimorphic cell states in the mouse kidney.
Specific Aim 3 will compare sexual dimorphism in the mouse with human kidney biopsies, integrating data generated in the proposal into the framework of KidneyCellExplorer (https://cello.shinyapps.io/kidneycellexplorer/) for viewing and analysis of the data.
There is a growing consensus that men and women differ in their response to kidney injury, and their susceptibility and progression to chronic kidney disease. We will combine powerful single cell technologies with genetic studies to determine how distinct male and female cell types are generated in the mouse kidney and how these are modified during reproduction. Comparative analysis on human kidney datasets will identify shared, and species-specific, sex programs in the male and female kidney.
