The role of Cldn10a in kidney injury susceptibility

• Applicants: Professorin Dr. Dorothee Günzel; Professor Dr. Kai Schmidt-Ott
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547091997

Following acute kidney injury (AKI), structural changes occur throughout renal tubules. The proximal tubule is the tubule segment most prone to ischemic injury. The paracellular anion channel-forming claudin-10a (Cldn10a) is specifically expressed in the proximal tubule. Our recent data indicate that Cldn10a loss in mice disrupts paracellular chloride transport and activates energy-producing pathways in kidney tubules. Moreover, preliminary data show that female mice express higher levels of proximal tubular Cldn10a than males and that proximal tubular Cldn10a expression is down-regulated after human and mouse acute kidney injury. We hypothesize that 1.) proximal tubular Cldn10a determines susceptibility and sex-specific outcomes after acute ischemic kidney injury in mice, 2.) proximal tubular Cldn10a has direct cell-autonomous functions to impact hypoxia-responses in isolated proximal tubule cells, and that 3.) understanding the transcriptional networks up- and downstream of proximal tubule tight junction-associated signaling will provide fundamental insights into the biological mechanisms that confer renal energy homeostasis and resilience to injury. We will address these hypotheses by Cldn10a-expressing and Cldn10a-deficient in vivo and in vitro models for ischemic renal injury, physiological assessments, unbiased single-cell transcriptome and chromatin accessibility studies, and semi-high throughput CRISPR interference screening.

• DFG Programme: Research Grants