The population of humans born preterm (~24-37 w gestation) is growing rapidly as a result of advanced medical care. Unfortunately, humans born before 36 w gestation have incomplete kidney development and low nephron numbers, which has been hypothesized to cause increased risk of chronic kidney disease (CKD) and hypertension later in life. Premature infants also have a high incidence of acute kidney injury (AKI). Due to limited animal models and few kidney biopsy samples, the pathogenesis of AKI and CKD as well as the cellular response to kidney injury and repair in this population is poorly understood. We have developed new mouse models of congenital low nephron numbers (50-70% of controls) by inhibiting Ret tyrosine kinase during kidney development. Preliminary studies showed that kidneys with low nephron numbers had an accelerated AKI to CKD transition following ischemia-reperfusion injury (IRI). Since low nephron numbers is known to cause glomerular hyperfiltration and higher metabolic demands for absorption of high filter load of Na+ at the single nephron level, we examined kidneys for stress response with autophagy. We found that kidneys with low nephron numbers were more hypoxic and had higher autophagic response 4 w post-IRI. Therefore, we have planned studies to test the following hypotheses: 1) Low renal reserve in underdeveloped kidneys contributes to high risk of CKD, and 2) High metabolic stress may exceed autophagic compensation and lead to CKD development.
Aim 1 will generate and validate new mouse models with a range of low nephron numbers (25-70% of control) that resemble human underdeveloped kidneys. We will take novel chemical and genetic approaches using mice harboring a floxed and mutant Ret allele that renders it susceptibility to a small molecule inhibitor. We plan to inhibit the engineered Ret activity with the chemical inhibitor or delete Ret gene specifically in the ureteric bud during mid-late gestation. Kidney development and renal structure and function will be characterized.
Aim 2 We will use these new mouse models to address the questions of whether kidneys with low nephron numbers: 1) are more susceptible to AKI with more severe injury and incomplete recovery, and 2) have increased risk of CKD in the absence of prior history of AKI or more rapid CKD development after AKI exposure. We will also study clinically relevant models of neonatal AKI using newborn mice with low nephron number to test the impact of AKI on the developing kidneys.
Aim 3 will characterize autophagy as a stress response to hypoxia and metabolic perturbations in underdeveloped kidneys by examining the role of autophagy in cell quality control as well as during the AKI to CKD transition. Studies are designed to test whether a decline in autophagic capacity and flux in response to physiologic and pathologic stress contributes to CKD development, and whether reducing metabolic stress delays CKD development. The overall goal is to obtain much needed knowledge that could be used in the future to prevent and treat kidney disease in the growing population of humans born preterm.

Public Health Relevance

Each year, 15 millions of premature babies are born and a vast majority of them survive. Because humans born preterm have low kidney reserve due to underdeveloped kidneys, it has been hypothesized for decades that low renal reserve contributes to high risk of chronic kidney disease and hypertension later in life. We have now generated mouse models of low numbers of functional unit in the kidney called nephron to understand biology of chronic kidney disease in the growing population of humans born preterm.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Hoshizaki, Deborah K
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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