# Identification of Common Genes Regulated by ER Stress During the Development of Diabetic Nephropathy Based on Human Transcriptome Datasets and an In Vivo Mouse Model

## TL;DR

This study explores how ER stress contributes to diabetic kidney disease and shows that inhibiting ER stress with 4-PBA improves kidney health in a mouse model.

## Contribution

The study identifies novel molecular pathways regulated by ER stress in diabetic nephropathy and validates 4-PBA as a potential therapeutic agent.

## Key findings

- 4-PBA treatment reduces albuminuria, podocyte loss, and renal inflammation in diabetic mice.
- ER stress inhibition with 4-PBA increases autophagy and decreases ER stress markers in diabetic kidneys.
- 4-PBA attenuates chronic renal dysfunction by targeting the complement C1q pathway and NADPH oxidase complex.

## Abstract

Diabetic nephropathy (DN) is a serious complication in diabetic patients, leading to kidney dysfunction and ultimately end-stage renal disease. Although several pharmacological agents have been developed, treating DN remains challenging due to its complex and multifaceted pathogenesis. Endoplasmic reticulum (ER) stress plays a crucial role in DN pathology; however, the molecular mechanisms underlying reduced ER stress remain poorly understood. This study investigated the protective effects of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, on DN and the related regulatory molecules through gene expression network analysis. A C57BL/6 mouse model of DN was used in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with 4-PBA by intraperitoneal injection for 6 weeks. The 4-PBA treatment effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, and renal inflammation and cell death. These changes induced by 4-PBA were associated with decreased expression of ER stress markers and increased autophagy activities in diabetic kidneys. Importantly, 4-PBA reduced components of the complement C1q pathway, the NADPH oxidase complex, and chemokines, thereby attenuating chronic renal dysfunction. Conclusively, inhibition of ER stress is a promising pharmacological target for treating patients with DN.