A new study headed by Dr. Monica Chang-Panesso, MD, Nephrology, revealed unexpected findings in an investigation of Meis1, a transcription factor that is required for mammalian development.
Meis1 is a known marker of interstitial stroma in the developing kidney. Defects in kidney development are seen in Meis1 mutant embryos. The homeobox protein plays an important role in tumorigenesis (solid tumors and leukemia) and is a regulator of postnatal cardiomyocyte cell cycle arrest. In the latter, the effects of Meis1 are mediated, in part, by the tumor suppressor protein p16INK4a.
Because p16INK4a is known to accumulate in the aging kidney, Dr. Chang-Panesso, Instructor of Medicine, hypothesized that Meis1 may regulate stromal proliferation during renal injury and aging.
Recently published ahead of print in AJP-Renal Physiology, this study is the first to show that Meis1 is specifically expressed in stroma and myofibroblasts of mouse and human kidney and is upregulated with kidney injury and aging.
Surprisingly, however, given the specific expression of Meis1 in kidney stroma during development and its upregulation in injury and aging, deletion of Meis1 had no effect on murine kidney fibrosis, a potential outcome of failed repair and seen during renal aging.
Two models of Meis1 deletion (a global deletion and a stroma-specific model) failed to show any kidney phenotype in development, homeostasis, injury response and in aging. The lack of phenotype with Meis1 deletion may be due to Meis family member redundancy (Meis2 and Meis3) or to the presence of a transcriptional binding partners to which Meis1 normally forms a heteromeric complex.
Another unexpected observation was that Meis1 knockout mice showed strong, specific upregulation of the tubular injury marker Kim-1, despite having normal kidney histology. Investigating further, they found that BALB/c mice also unexpectedly express baseline Kim-1 protein without kidney abnormality. They conclude that since the Meis1 and Kim-1 genes are located near each other on the same chromosome, they are in “linkage disequilibrium”, the non-random association of alleles at different loci in a given population.
“The study provides insight into Meis1 as a possible pericyte marker given its presence in the perivascular niche; however, further studies are needed to confirm this observation,” says Dr. Chang-Panesso. “Its use as a stromal marker can facilitate quantitation given its nuclear expression.”
The article titled Meis1 is Specifically Upregulated in Kidney Myofibroblasts During Aging and Injury but is Not Required for Kidney Homeostasis or Fibrotic Response can be read here. Authors: Monica Chang-Panesso, Farid F. Kadyrov, Flavia G. Machado, Ashish Kumar, and Benjamin D. Humphreys.