TY - JOUR
T1 - Mice with Established Diabetes Show Increased Susceptibility to Renal Ischemia/Reperfusion Injury
T2 - Protection by Blockade of Jnk or Syk Signaling Pathways
AU - Grynberg, Keren
AU - Tian, Lifang
AU - Tesch, Greg
AU - Ozols, Elyce
AU - Mulley, William R.
AU - Nikolic-Paterson, David J.
AU - Ma, Frank Y.
N1 - Funding Information:
Disclosures: D.J.N.-P. has previously received funding from Celgene for studies on JNK inhibitors. Celgene played no part in the design, analysis, interpretation, or funding of these experiments.
Funding Information:
Sponsored by National Health and Medical Research Council of Australia grant 1156982 (D.J.N.-P. and F.Y.M.) and a Royal Australian College of Physicians Jacquot PhD Scholarship (K.G.).
Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/3
Y1 - 2022/3
N2 - Patients with diabetes are at an increased risk for acute kidney injury (AKI) after renal ischemia/reperfusion injury (IRI). However, there is a lack preclinical models of IRI in established diabetes. The current study characterized renal IRI in mice with established diabetes and investigated potential therapies. Diabetes was induced in C57BL/6J mice by low-dose streptozotocin injection. After 7 weeks of sustained diabetes, mice underwent 13 minutes of bilateral renal ischemia and were euthanized after 24 hours of reperfusion. Age-matched, nondiabetic controls underwent the same surgical procedure. Renal IRI induced two- and sevenfold increases in plasma creatinine level in nondiabetic and diabetic mice, respectively (P < 0.001). Kidney damage, as indicated by histologic damage, tubular cell death, tubular damage markers, and inflammation, was more severe in the diabetic IRI group. The diabetic IRI group showed greater accumulation of spleen tyrosine kinase (Syk)-expressing cells, and increased c-Jun N-terminal kinase (Jnk) signaling in tubules compared to nondiabetic IRI. Prophylactic treatment with a Jnk or Syk inhibitor substantially reduced the severity of AKI in the diabetic IRI model, with differential effects on neutrophil infiltration and Jnk activation. In conclusion, established diabetes predisposed mice to renal IRI-induced AKI. Two distinct proinflammatory pathways, JNK and SYK, were identified as potential therapeutic targets for anticipated AKI in patients with diabetes.
AB - Patients with diabetes are at an increased risk for acute kidney injury (AKI) after renal ischemia/reperfusion injury (IRI). However, there is a lack preclinical models of IRI in established diabetes. The current study characterized renal IRI in mice with established diabetes and investigated potential therapies. Diabetes was induced in C57BL/6J mice by low-dose streptozotocin injection. After 7 weeks of sustained diabetes, mice underwent 13 minutes of bilateral renal ischemia and were euthanized after 24 hours of reperfusion. Age-matched, nondiabetic controls underwent the same surgical procedure. Renal IRI induced two- and sevenfold increases in plasma creatinine level in nondiabetic and diabetic mice, respectively (P < 0.001). Kidney damage, as indicated by histologic damage, tubular cell death, tubular damage markers, and inflammation, was more severe in the diabetic IRI group. The diabetic IRI group showed greater accumulation of spleen tyrosine kinase (Syk)-expressing cells, and increased c-Jun N-terminal kinase (Jnk) signaling in tubules compared to nondiabetic IRI. Prophylactic treatment with a Jnk or Syk inhibitor substantially reduced the severity of AKI in the diabetic IRI model, with differential effects on neutrophil infiltration and Jnk activation. In conclusion, established diabetes predisposed mice to renal IRI-induced AKI. Two distinct proinflammatory pathways, JNK and SYK, were identified as potential therapeutic targets for anticipated AKI in patients with diabetes.
UR - http://www.scopus.com/inward/record.url?scp=85125189190&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2021.12.003
DO - 10.1016/j.ajpath.2021.12.003
M3 - Article
C2 - 34954209
AN - SCOPUS:85125189190
VL - 192
SP - 441
EP - 453
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 3
ER -
