A Case-Inspired Exploration of Renin Mutations in Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD): Not All Paths Lead to the ER.

Abstract Background: Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) results from mutations in various genes, including REN , UMOD , MUC1 , and HNF1B . ADTKD-REN is often characterized as a proteinopathy that triggers the endoplasmic reticulum stress (ERS) cascade, potentially sharing similarities with ADTKD-UMOD and ADTKD-MUC1 at the cellular level. Inspired by a patient with a W17R mutation, we aimed to investigate ERS activation caused by this and two other renin variants (W10R and L381P). Additionally, we explored potential molecular commonalities with other TKD forms, specifically ADTKD-HNF1B and MITKD (Mitochondrially Inherited Tubulointerstitial Kidney Disease). Methods: We established stable cell lines expressing wild-type renin and its mutated forms: W17R, W10R, and L381P. Using luciferase reporter constructs, RT-qPCR, and confocal imaging, we conducted tests to evaluate ERS activation, TGFβ upregulation, and the cellular localization of various renin variants. Results: The L381P line exhibited signs of ERS activation and transcriptional upregulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and CRELD2 (cysteine-rich with EGF-like domains 2). ERS activation was not observed in the W17R line, while the W10R line displayed intermediate features. None of the lines upregulated TGFβ. Importantly, the W17R variant was misdirected to the mitochondria. Conclusion: Individuals with the L381P mutation may benefit from research on ADTKD-UMOD and ADTKD-MUC1 treatments. The pathogenic mechanism of the W17R mutation involves mitochondria rather than the ER pathway, thus may potentially overlap with MITKD. We propose testing CRELD2 and MANF as markers to target therapies for a specific subgroup of ADTKD-REN patients.