Ananna Kazi Research Presentation Final
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Transcript of Ananna Kazi Research Presentation Final
Loss of Par-1a/b Polarity Proteins Leads to Increased Susceptibility to Acute Kidney Injury in Mice Ananna Kazi
Student, Junior Year, Binghamton University
Frederick Kaskel, MD, PHD and Kimberly Reidy, MD, Pediatric
Nephrology, Children’s Hospital at Montefiore/
Albert Einstein College of Medicine
A Patient I Saw• 19 day old baby girl with heart defect
underwent heart surgery• Creatinine 0.4 to 1.0 mg/dL (Estimated
glomerular filtration rate 19) • Urine output decreased
– Swollen body
Acute Kidney Injury (AKI)• Sudden inability of kidneys to filter
waste product from blood. • 5% to 7% of all patients admitted to
general medical-surgical hospitals have AKI. (Mandelbaum, MD et al., 2012)
• 20 to 50% of patients in Intensive Care Units (ICUs) develop AKI. (Case et al., 2013)
• Children are at high risk of AKI. (Andreoli, MD, 2008)
Acute Kidney Injury (AKI)• Symptoms: o Decreased urine output leads to fluid
retention in the body causing swelling in legs, ankles or feet, shortness of breath or chest pain
o Accumulation of toxins causes drowsiness, fatigue, nausea, confusion, seizures, or coma in severe cases
• Complex electrolyte alterationso Hyperkalemiao Hypocalcemiao Hyperphosphatemia
Pathophysiology of AKI• Causes:
– Ischemia– Drugs
• Decreased glomerular filtration rate (GFR)o Increased creatinine and Blood Urea
Nitrogen (BUN)• Proximal tubules are affected
o High metabolic rate• Lower blood flow as with ischemia
–Lower level of oxygen» Low ATP
Effects of Sub-lethal Injury to Tubular Cells
Sharfuddin, A. A. & Molitoris, B. A. (2011) Pathophysiology of ischemic acute kidney injuryNat. Rev. Nephrol. doi:10.1038/nrneph.2011.16
Healthy Cells
Injured Cells
Cell Polarity and Polarity Proteins• Asymmetric expression of proteins in
different parts of cells o differences in cell shape, structure, and
function• Epithelial Cell Polarity
o Required for solute transportation in kidney
Partitioning Defective 1 • Par polarity protein family • Localizes to the basolateral aspect of cells.• Complete deletion of Par-1a/b (Par-1a-/-:Par-
1b-/-) leads to death early in fetal development of mice.
• Contributes to proximal tubular development in newborn mice
• Expressed in developing nephron• Decreased expression in adult nephron • Increased expression in tubular injury (cisplatin,
folic acid) in mice
Hypothesis• Par-1a/b are protective in the setting of
kidney injury.• To test this:
– Cisplatin injected in mice– light microscopy used to examine injury
Cisplatin Induced InjuryMouse at 5 weeks
3 Days after Injection
Par-1a-/-
Par-1b-/-
Controls
Sacrificed
Methods• Histology
o Hematoxylin and Eosin Stain
• Immunohistochemistryo Ki67
Mouse Anti-Ki67
Donkey Anti-Mouse
Modified Image from Wikipedia
Increased Tubular Injury in Par-1b Knockout Mice
Par-1b-/- Cisplatin Injected Control Non-injected Control
30 m
g/kg
20 m
g/kg
Dilated Proximal Tubules
Injury
Decreased Proliferation in Par-1b Knockout Mice
Par
-1b-
/-C
ispl
atin
Inje
cted
C
ontro
ls
Merge /HoechstLTLKi67
Conclusions• Par-1b polarity proteins contribute to
tubular epithelial response to injury.• Either decreased or delayed
proliferation may contribute to the increased tubular injury in Par-1b-/- mice.
References• Andreoli, S. P. (2009). Acute kidney injury in
children. Pediatric Nephrology (Berlin, Germany), 24(2), 253–263. doi:10.1007/s00467-008-1074-9
• James Case, Supriya Khan, Raeesa Khalid, and Akram Khan, “Epidemiology of Acute Kidney Injury in the Intensive Care Unit,” Critical Care Research and Practice, vol. 2013, Article ID 479730, 9 pages, 2013. doi:10.1155/2013/479730
• Mandelbaum, T., Scott, D. J., Lee, J., Mark, R. G., Malhotra, A., Waikar, S. S., … Talmor, D. (2011). Outcome of Critically ill Patients with Acute Kidney Injury using the AKIN Criteria. Critical Care Medicine, 39(12), 2659–2664. doi:10.1097/CCM.0b013e3182281f1b
• Molitoris, B. A., & Sharfuddin, A. A. (2011). Pathophysiology of ischemic acute kidney injury. Nature Reviews Nephrology, 7(4), 189+. Retrieved from http://go.galegroup.com.proxy.binghamton.edu/ps/i.do?id=GALE%7CA253446287&v=2.1&u=bingul&it=r&p=HRCA&sw=w&asid=b6d6782267fcd907c22c5b7acd497d78
Acknowledgements• APS STEP-UP Fellowship
• NIH NIDDK K08 5K08DK091507
• T32 DK007110
• Dr. Kaskel and Dr. Reidy
• Dr. Du, Dr. Pal, and Dr. Koral