Primary Research Focus
The Surendran Lab studies kidney development and disease by determining the molecular basis by which diverse cell types of the kidney develop and are maintained. The Surendran Lab uses novel genetic mouse models, along with cell and ex vivo organ cultures, to identify genes critical for kidney development and/or maintenance of kidney functions.
The Surendran Lab focuses on two areas:
- The molecular mechanisms regulating kidney collecting duct development and maintenance
- The cellular and genetic basis of kidney diseases associated with Alagille Syndrome patients.
The lab uses mouse genetic tools for ectopic expression, loss of function and cell lineage tracing studies in specific populations of cells of the developing mouse kidneys to understand the molecular regulators that ensure normal kidney development and maintenance. These studies have provided insights into the potential genetic and cellular causes of cystic kidney diseases, including those that occur in Alagille Syndrome patients and collecting duct disorders such as Nephrogenic Diabetes Insipidus. The lab has also identified transcription factors and signals that potentially regulate principal versus intercalated cell differentiation.
About the Surendran Lab
Lab Projects and News
The role(s) of mature kidney epithelial cell plasticity in renal physiology and pathology
Multicellular organisms develop and maintain diverse cell types to remain healthy. Considering mature cells can be instructed to become pluripotent stem cells, it is possible that diseases arise from the disruption of molecular mechanisms that ensure the stability of mature cell states. In the kidneys, which comprise of diverse cell types, mechanisms must be in place to maintain diverse epithelial cell types to prevent them from switching between cell types. Cell type conversion is hypothesized to occur within adult kidney collecting ducts of patients on lithium therapy for treatment of bipolar disorders and can result in acquired nephrogenic diabetes insipidus (NDI), which involves a urine-concentrating defect and in the long-term increases the likelihood of developing kidney failure.
We have determined that lithium treatment of adult mice or inhibition of Notch signaling in adult mouse kidney epithelial cell types causes the direct conversion of Aquaporin4 water channel expressing principal cell types into Foxi1 expressing intercalated cells. The Notch inhibition dependent cell type conversion does not involve DNA synthesis and appears to meet a strict definition of cell type transdifferentiation (PMC6317606).
Molecular regulators of kidney collecting duct differentiation
The kidney collecting ducts form a tubular network that develops from the repeated branching of the ureteric bud (UB). During branching, the epithelial cells of the UB differentiate into principal cell types and intercalated cell types. We are interested in understanding the molecular mechanisms that regulate collecting duct cell type selection and differentiation. It is known that Foxi1 is a critical transcription factor required for intercalated cell type differentiation. Interestingly, we have determined that repression of Foxi1 by Notch signaling via Hes1 is sufficient to allow for principal cell fate selection (10.1016/j.ydbio.2020.08.005).By examining the transcriptional profiles of kidneys with normal versus increased Notch signaling in the developing collecting ducts we have identified candidate regulators of principal versus intercalated cell differentiation. Among these are about 16 down regulated factors, including Foxi1, that are candidate intercalated cell factors (ICFs) and about 14 up regulated factors, including Elf5, that are candidate principal cell factors (PCFs). We have validated that Elf5 is specifically expressed in principal cells, and that it contributes to the expression of critical principal cell specific genes, such as Aqp2 (PMC5382981).
Determining the role of Notch in regulating tubule morphogenesis and the kidney diseases associated with Alagille Syndrome
Defective Notch signaling is associated with a multi-organ human disease including the kidneys termed Alagille Syndrome (ALGS). There are no therapies for the kidney disease in ALGS patients in part due to a lack of understanding of the cellular and molecular processes that are altered in ALGS kidneys. To better understand the ALGS associated kidney disease, we have generated mice with Notch signaling deficient kidneys, which develop small multi-cystic kidneys, similar to what occurs in ALGS patients. We are using these mice and cell culture models to understand the underlying cause of multi-cystic kidney disease in ALGS and have so far identified a role for Notch in regulating the orientation of cell division.