Researchers from Boston University School of Medicine have identified a gene inactivated in cases of chronic kidney disease (CKD) that could be a target for new treatments. Full details of their findings are described in a paper published in the American Journal of Pathology.
The paper explains how transmembrane and immunoglobulin domain containing 1 (TMIGD1) functions to protect kidneys and describes a mechanism by which accumulated toxins damage the kidney. TMIGD1 is a protein-coding gene that is expressed mostly in the cytosol and membrane of renal tubular epithelial cells. It is involved in several cellular processes including the regulation of cell migration and membrane permeability. There is evidence that TMIGD1 “protects tubular cells and promotes survival,” the researchers wrote. “However, the direct role of TMIGD1 in CKD and mechanisms of [its] regulation in renal tubular epithelial cells remain unaddressed.”
Statistics from the U.S. Centers for Disease Control and Prevention estimate that about 37 million U.S. adults have CKD and that most are undiagnosed. If it isn’t treated quickly, CKD can progress to kidney failure and early cardiovascular disease. “The novelty of our finding is the contribution of the TMIGD1 gene to kidney failure,” Vipul Chitalia, MD, PhD, associate professor of medicine at BU and corresponding author on the paper, said in a statement. Also, “we have deciphered how toxins contribute to kidney failure, thereby worsening renal function.”
In the study, the scientists used knockout mice and various rodent models of CKD to show that when toxins inactivated TMIGD1, the models were more susceptible to injury. They used two tubulotoxins—indoxyl sulfate and kynurenine—which suppress TMIGD1 transcription in tubular cells. The two toxins are types of uremic solutes that appear in the early stages of CKD and increase as the condition progresses.
The data showed that inactivating TMIGD1 “significantly lowered acetylated tubulin, decreased tubular cell proliferation, caused severe tubular damage, and worsened renal function,” the paper stated. The results also suggest that the downregulation of TMIGD1 gene expression in the renal tubules was not due to a “reduction in renal tubular mass.”
Further studies on this topic could focus on exploring TMIDG1 regulation of the mitotic spindle in renal tubules after kidney injury or its role in the transition from acute kidney injury to CKD. Ultimately, the researchers hope their findings will lead to new treatments that protect renal tubules in CKD and reduce disease incidence. In addition to serving as a treatment target, TMIGD1 could be used as to screen for kidney damage, noted Wenqing Yin, MD, PhD, the co-first author on the paper and an American Heart Association fellow.
