Investigating sex-related differences in renal tissues from prohibitin-1 knock-in mouse models

Abstract

Biological sex-related differences are present in many aspects of renal biology and pathobiology. However, our knowledge of the underlying mechanisms is currently limited. Prohibitin-1 (PHB1) is an evolutionarily conserved pleiotropic protein. Transgenic mouse models of PHB1 have revealed its role in sex differences in adipose and immune functions. However, it is not known whether PHB1 plays a role in sex differences in other cell and tissue types. To explore this at the systemic level, we focused on two key conserved post-translational modification sites in PHB1 (i.e., the Cys69 and Tyr114 residues) and developed Phb1C69A and Phb1Y114F knock-in mouse models (together referred to as the Phb1-Ki mice, unless specified separately). The Phb1-Ki mice displayed both similarities and dissimilarities in sex differences in their immunometabolic phenotypes, signifying the importance of Cys69- and Tyr114-linked functions in the sexually dimorphic features of PHB1. Interestingly, an increase in kidney mass was found in the Phb1-Ki mice. The Phb1-KiY114F mice had significantly larger kidneys than the Phb1-KiC69A mice and wild-type mice. Further analysis of kidney samples from the Phb1-Ki mice showed structural differences in renal tubules and glomeruli. Particularly, a dysregulation of mitochondrial structure in tubular epithelial cells and increase in glomerular size was observed, which were more pronounced in the male Phb1-KiY114F mice. Moreover, lipid droplets were frequently encountered in tubular epithelial cells from the male Phb1-KiC69A mice, whereas an accumulation of damaged mitochondria and immune cell infiltration were more apparent in the male Phb1-KiY114F mice. Notably, sex differences in ubiquitin proteasome activity was apparent between the wild-type male and female mice, which was differently affected in renal tissues from the male and female Phb1-Ki mice and inversely correlated with the accumulation of the damaged mitochondria in tubular epithelial cells. In addition, sex-related differences in IGF1 receptor-mTOR singling and in the markers of mitochondrial dynamics were found in the Phb1-Ki mice, which were differently altered in the Phb1-KiC69A mice and Phb1-KiY114F mice. These cellular and molecular changes correlated with the observed changes at the organ level, including sex-related differences. Collectively, the research findings herein suggest that PHB1’s Cys69- and Tyr114-linked functions play a role in sex differences in renal biology, which was previously unknown. The Phb1-Ki mouse models have created new opportunities to advance our understanding in this field. A better understanding of sex differences in renal biology and pathobiology may open opportunities for better management and treatment of renal diseases, which is a prevalent health problem worldwide.