# Dietary Polyunsaturated Fatty Acid Deficiency Impairs Renal Lipid Metabolism and Adaptive Response to Proteinuria in Murine Renal Tubules

## TL;DR

This study shows that a lack of polyunsaturated fatty acids (PUFAs) in the diet can impair kidney function and worsen proteinuria in mice.

## Contribution

The study reveals a novel role for PUFAs in supporting renal tubular adaptive responses to proteinuria through PPARα-mediated lipid metabolism.

## Key findings

- A PUFA-deficient diet increased urinary protein excretion and disrupted renal energy homeostasis in mice under protein overload.
- PUFA supplementation at physiological levels attenuated these adverse effects and restored PPARα-mediated responses.
- The absence of PUFAs suppressed adaptive endocytosis and worsened lipid metabolism in renal tubules.

## Abstract

Background/Objectives: Kidneys are fatty acid (FA)-consuming organs that use adenosine triphosphate (ATP) for tubular functions, including endocytosis for protein reabsorption to prevent urinary protein loss. Peroxisome proliferator-activated receptor α (PPARα) is a master regulator of FA metabolism and energy production, with high renal expression. Although polyunsaturated fatty acids (PUFAs) are essential nutrients that are natural PPARα ligands, their role in tubular protein reabsorption remains unclear. As clinical PUFA deficiency occurs in humans under various conditions, we used a mouse model that mimics these conditions. Methods: We administered a 2-week intraperitoneal protein-overload (PO) treatment to mice that had been continuously fed a PUFA-deficient diet. We compared the phenotypic changes with those in mice fed a standard diet and those in mice fed a PUFA-deficient diet with PUFA supplementation. Results: In the absence of PO, the PUFA-deficient diet induced increased lysosomal autophagy activation; however, other phenotypic differences were not detected among the diet groups. In the PO experimental condition, the PUFA-deficient diet increased daily urinary protein excretion and tubular lysosomes; suppressed adaptive endocytosis activation, which was probably enhanced by continuous autophagy activation; and worsened FA metabolism and PPARα-mediated responses to PO, which disrupted renal energy homeostasis. However, these changes were attenuated by PUFA supplementation at the physiological intake level. Conclusions: PUFAs are essential nutrients for the tubular adaptive reabsorption response against urinary protein loss. Therefore, active PUFA intake may be important for patients with kidney disease-associated proteinuria, especially those with various PUFA deficiency-inducing conditions.