# The Influence of Sex and Hormones on Organelle Stress in Kidney Injury: Insights from Preclinical Models

## TL;DR

This paper reviews how biological sex and hormones influence organelle stress in kidney cells, explaining sex-based differences in kidney disease progression.

## Contribution

It synthesizes preclinical evidence on how sex and hormones affect mitochondrial, endoplasmic reticulum, and ciliary stress in kidney disease.

## Key findings

- Male hormones like androgens accelerate kidney function decline in men.
- Female hormones provide protection against kidney disease that diminishes after menopause.
- Organelle stress in mitochondria, endoplasmic reticulum, and cilia contributes to sex-specific kidney disease outcomes.

## Abstract

Kidney disorders are influenced by many factors, but biological sex and hormones play important roles in many diseases that affect the kidney, showing clear differences between men and women. Chronic Kidney Disease, for example, is more common in women, yet men often lose kidney function faster, partly because male hormones can worsen disease progression. After menopause, women lose some of the protective effects of female hormones, which further highlights how sex influences vulnerability to kidney problems. Kidney cells face many kinds of everyday and disease-related stress. At first, the cells can adjust to these challenges, but if the stress continues, it can overwhelm important parts of the cell. Organelles are cell structures such as mitochondria, the cell’s energy center; the endoplasmic reticulum, which helps make and fold proteins; and primary cilia, small cellular sensors. Organelles work together to maintain cell metabolism and kidney function, but when they are stressed, the cell’s normal activities and communication break down, leading to problems such as reduced energy, inflammation, and scarring. This is a review of animal studies that describe how sex and hormones affect stress in cellular organelles and how these differences may help explain why men and women may experience kidney disease differently.

Kidney cells are exposed to a wide range of physiological and pathological stresses, including hormonal changes, mechanical forces, hypoxia, hyperglycemia, and inflammation. These insults can trigger adaptive responses, but when they persist, they can lead to organelle stress. Organelles such as mitochondria, the endoplasmic reticulum, and primary cilia sustain cellular metabolism and tissue homeostasis. When organelle stress occurs, it disrupts cellular processes and organelle communication, leading to metabolic dysfunction, inflammation, fibrosis, and progression of kidney disease. Sex and hormonal factors play a significant role in the development of renal disorders. Many glomerular diseases show distinct differences between the sexes. Chronic Kidney Disease is more common in women, while men often experience a faster decline in kidney function, partly due to the influence of androgens. Additionally, the loss of female hormonal protection after menopause highlights the importance of sex as a factor in renal susceptibility. This narrative review synthesizes preclinical evidence on how sexual dimorphism and sex hormones affect organelle stress in mitochondria, the endoplasmic reticulum, and primary cilia, from 33 studies identified through a non-systematic literature search of the PubMed database, to provide an overview of how these mechanisms contribute to sex-specific differences in kidney disease pathophysiology.