Bottom line: RAAS inhibition not just lowers pressure. It reshapes a pathological conversation btw/ distal nephron & inflammatory macs. And single-cell biology is no longer about making prettier atlases. It is about correcting assumptions we have been carrying for decades.

🧪Paper: t.ly/oNjkJ

The human data brought it home. Higher CTSD expr. in kidney tubules tracked w/ worse eGFR & more fibrosis. Patients on RAASi had lower CTSD. And a gene signature derived from enalapril-responsive cells stratified kidneys by outcomes, not diagnoses. Mechanism meeting prognosis is always satisfying.

Spatial transcriptomics sealed it. In human DKD kidneys, CTSD⁺ connecting tubules and TREM2⁺ macrophages sit next to each other. Not metaphorically. Physically. When disease is present, their neighborhood expands. When RAAS signaling is suppressed, that neighborhood quiets down. Context matters.

Then came the immune system. Those CTSD⁺ distal cells were talking — loudly — to a specific macrophage population: TREM2⁺ resident macrophages. These macrophages were inflammatory, expanded in DKD, and shrank with enalapril treatment. This was epithelial–immune crosstalk, not collateral damage.

Digging deeper, we found a distinct population of CTSD⁺ connecting tubule cells. They sit between healthy and injured states. Not fully broken, not fully normal. Transitional. Plastic. Vulnerable. And enalapril selectively depleted this population. That was the first “oh wow” moment.

One molecule kept showing up: cathepsin D (CTSD). Strongly induced in diabetic kidneys. Strongly suppressed by enalapril. And not everywhere — very specifically in a subset of distal nephron cells. This was not a generic injury marker. It looked like a state.

When we mapped the kidney cell by cell, the biggest enalapril “rescue” signal was not in proximal tubules. It was in the distal nephron. That alone made us stop and reread the plots twice.

Using long-term enalapril treatment in the ZSF1 rat DKD model, we confirmed the obvious first: blood pressure, albuminuria, fibrosis, injury markers all improved. So yes, the drug works. But where does it work? That question is where single-cell really earns its keep.

RAAS inhibitors have been used for decades. We all learned the story: glomeruli, proximal tubules, hemodynamics. But when we looked at this with single-cell resolution, the biology told a different story. Not louder. Just clearer. And it pointed us somewhere unexpected.

Well deserved, Rafael! Congrats!

Thx, Rebecca!

Thanks, Tilo! 👍

💯👍

Thanks, Lennard! 🙏