Effects of Par1a Deletion on Tubulointerstitial Fibrosis in Folic Acid Mouse Models of Renal Injury

Chronic Kidney Disease (CKD) affects 1 out of 7 adults in the United States and causes significant morbidity and mortality. Development of tubulointerstitial fibrosis, and the accompanying loss of functional tubular cells, leads to CKD progression. The Notch signaling pathway is required for renal development, however, sustained Notch activation in adult mice induces tubulointerstitial fibrosis. Dual deletion of Par1a and Par1b, serine threonine kinases, in developing mouse kidneys impaired Notch activation and resulted in the formation of abnormal glomeruli and proximal tubules. Deletion of either Par1a or 1b does not affect kidney development.We hypothesize that Par1a or 1b deletion in mice would protect against folic acid (FA) induced tubulointerstitial fibrosis. FA models of renal fibrosis were induced in Par1a WT and Par1a KO mice with intraperitoneal injections of 250 mg/kg FA dissolved in 300 nM NaHCO3. Mice were examined 7 days after injection—the time of earliest fibrosis and peak Notch expression. Sirius red collagen staining was used to quantify the severity of fibrosis. Immunohistochemical staining for Notch signaling components and Par1a were performed. It was observed that Par1a expression was increased after FA injection. Par1a colocalized in tubules with increased Jag1 expression. Sirius red staining demonstrated less fibrosis in Par1a KO vs. WT mice. Together, our results suggest Par1a deletion may be protective against renal fibrosis. Par1-Notch interactions may be mediated by effects on Jag1. Par1-Notch signaling could be a novel target for therapeutic intervention and potentially attenuate CKD progression

Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth

Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants

Developing a Research Mentorship Program: The American Society of Pediatric Nephrology's Experience

Background: Most pediatric nephrologists work in academia. Mentor-mentee relationships provide support and guidance for successful research career. Mentorship program implementation is valuable in medical fields for providing research opportunities to young faculty. Methods: The American Society of Pediatric Nephrology (ASPN) established a research mentorship program to (a) assist with matching of appropriate mentor-mentee dyads and (b) establish metrics for desirable mentor-mentee outcomes with two independent components: (1) the grants review workshop, a short-term program providing mentor feedback on grant proposals, and (2) the longitudinal program, establishing long-term mentor-mentee relationships. Regular surveys of both mentors and mentees were reviewed to evaluate and refine the program. Results: Twelve mentees and 17 mentors participated in the grant review workshop and 19 mentees were matched to mentors in the longitudinal program. A review of NIH RePORTER data indicated that since 2014, 13 NIH grants have been awarded. Mentees in the longitudinal program reported that the program helped most with identifying an outside mentor, improving grant research content, and with general career development. Mentors perceived themselves to be most helpful in assisting with overall career plans. Email communications were preferred over phone or face-to-face communications. Mentees endorsed strong interest in staying in touch with their mentors and 100% of mentors expressed their willingness to serve in the future. Conclusion: This mentorship program was initiated and supported by a relatively small medical society and has shown early success in cultivating mentoring relationships for a future generation of clinician-scientists

Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis

Background and objectives: African American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression and cardiovascular morbidity in children. Design, setting, participants, & measurements: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.Results: A total of 140 AA children in the CKiD study were genotyped. HR APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p 3 mg/L (33% vs. 15%, p=0.12) and obesity (48% vs. 19%, p=0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. Conclusions: AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of CKD and LVH management in this population

Pathophysiology of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. This article reviews some of the experimental and clinical data on the pathophysiology of FSGS

Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome.

Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome

Compensation of Academic Research Computing and Data Professionals

Previous work identified low compensation levels as a barrier to recruitment and retention in the Research Computing and Data (RCD) field. In order to better understand the characteristics of RCD compensation, a 2021 survey of RCD professionals in the United States gathered salary information from 480 full-time, currently-employed RCD professionals, including 394 respondents working at non-medical academic institutions. The median salary reported for academic institutions was $90,000 ($80,000 for individual contributor levels), with variation observed across respondents' position levels, gender, ethnicity, education, years of experience, and geography. While RCD roles require a combination of expertise in two fields - research and technology - the median compensation for academic RCD professionals falls below that for either of these fields independently. The variation in compensation within the academic RCD field is also found to be less than the variation in the non-academic technology industry or for academic research faculty positions, with salary ranges limited at the upper end. Smaller differences in compensation between respondents based on years of experience and education were observed compared to the broader labor market. Further research with data from more RCD professionals is needed for a complete analysis of compensation within the RCD field.National Science FoundationImmediate accessThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]