Breakthrough research identifies key microenvironments linked to kidney injury and disease

Keck School of Medicine of USCSep 5 2024

A study published in Nature Communications provides new insight into how damaged cells interact within disease-promoting microenvironments following acute kidney injury, or AKI. With limited treatment options, AKI frequently progresses to chronic kidney disease (CKD), which affects more than 1 in 7 U.S. adults-;an estimated 37 million people.

The new findings may contribute to future efforts to prevent CKD, which can lead to kidney failure. 

The study brought together scientists from Andy McMahon's lab at USC and Long Cai's lab at Caltech, with support from a USC Broad Innovation Award that funded the cross-institutional research collaboration. 

In the study, co-first authors Michal Polonsky from Caltech and Louisa Gerhardt from USC, leveraged a cutting-edge tool, called seqFISH, developed in the Cai laboratory. With this tool, researchers can gather information about genetic activity and study cellular interactions in intact kidney tissue in mice with AKI. This allowed the scientists to analyze the precise expression of over 1,000 genes in the injured kidney tissue, identify microenvironments associated with injury, and predict cellular interactions associated with the progression to CKD.

"Dr. Cai's seqFISH technology provides unprecedented insight into the cellular interplay in the kidney following injury," said McMahon, who is the W.M. Keck Provost and University Professor of Stem Cell Biology and Regenerative Medicine at USC and will join the faculty of Caltech in October. "A better understanding of kidney injury is needed to identify targets for preventing the progression to chronic kidney disease."

Cai, who is a Professor of Biology and Biological Engineering, added: "We're thrilled that our technology has enabled a deeper understanding of kidney injury and disease. This study exemplifies the importance of cross-institutional and cross-disciplinary collaborations to advance biomedical research." 

In the kidney's outermost layer, the scientists identified a likely pathological microenvironment, which they dubbed "ME-5." This microenvironment contained a type of kidney cell particularly vulnerable to injury, known as a proximal tubule cell or PT. 

In ME-5, injured PTs and neighboring connective tissue cells, known as fibroblasts, exchanged signals that could drive injury progression. Key signals involved the genes Clcf1 and Crfl1, which encode proteins that can promote inflammation and fibrosis, or scarring. Additional signals detected in ME-5 could contribute to recruitment of immune cells, thereby further contributing to development of inflammation, fibrosis and other pathological changes.

The scientists also identified another important injury-associated microenvironment, which they named "ME-16," featuring aggregations of various immune cell types called tertiary lymphoid structures that are known to contribute to chronic inflammation. Rather than being confined to a specific region of the kidney, ME-16 was distributed throughout the injured organ. 

To share their discoveries, the team constructed a comprehensive map of cellular, molecular, and structural changes following AKI, which refines our understanding of the transition to CKD. This map is publicly available at https://woldlab.caltech.edu/ci2-celltiles/Mouse-Kidney-Fibrosis/.

Additional co-authors are Kari Koppitch from USC; Jina Yun, Katsuya Lex Colón, Henry Amrhein, Matt Thomson, and Barbara Wold from Caltech; and Shiwei Zheng and Guo-Cheng Yuan from the Icahn School of Medicine at Mount Sinai.

In addition to the USC Broad Innovation Award, the research was supported by the National Institutes of Health (grant NIDDK UC2DK126024), German Research Foundation (grant GE 3179/1-1), and German Society of Internal Medicine (DGIM) Clinician Scientist Grant.