# Gastrodin alleviates high fructose-induced podocyte mitochondria-mediated apoptosis by inhibiting NLRP6 to facilitate TRIM7-triggered Bok mRNA degradation

## TL;DR

Gastrodin protects kidney cells from high fructose damage by reducing NLRP6 and preventing mitochondria-related cell death.

## Contribution

This study reveals a novel mechanism of podocyte injury and identifies gastrodin as a potential treatment by targeting NLRP6.

## Key findings

- High NLRP6 expression contributes to podocyte mitochondria-mediated apoptosis in high fructose conditions.
- Gastrodin reduces NLRP6 and mitigates mitochondrial apoptosis by promoting TRIM7-triggered Bok mRNA degradation.
- NLRP6 deficiency or suppression ameliorates podocyte injury and mitochondrial dysfunction in mice.

## Abstract

Mitochondria-mediated apoptosis is the key determinant of glomerular podocyte injury. NOD-like receptor family pyrin domain proteins (NLRPs) are aberrant in clinical kidney diseases, but the role in podocyte mitochondrial dysfunction is unclear. Here, we first observed only NLRP6 expression change in nephrotic syndrome patients with proteinuria. Next, we found that mouse glomerular podocyte NLRP6 expression was increased in high fructose-induced proteinuria with mitochondria-mediated apoptosis. Importantly, Nlrp6 deficiency ameliorated these disturbances in mice. NLRP6 downregulation inhibited podocyte mitochondrial outer membrane permeabilization (MOMP)-associated apoptosis via suppressing B-cell lymphoma 2-related ovarian killer (BOK) under high fructose stimulation. However, high NLRP6 expression blocked the binding of Tripartite motif-containing protein 7 (TRIM7) with Bok mRNA 3' untranslated region, decreased mRNA decay, and thereby downregulated antioxidant protein family with sequence similarity 213, member A (FAM213A), resulting in mitochondria-mediated apoptosis in high fructose-exposed podocytes. A nephroprotective agent gastrodin was found to decrease NLRP6 and relieve mitochondria-mediated apoptosis caused by high fructose, possibly through promoting TRIM7-driven Bok mRNA degradation and FAM213A antioxidant effect. This study uncovered that high NLRP6 expression-driven mitochondria-mediated apoptosis could participate in podocyte injury and the suppression of NLRP6 by gastrodin may be an attractive therapeutic approach for podocyte injury.