Mice with Established Diabetes Show Increased Susceptibility to Renal Ischemia/Reperfusion Injury: Protection by Blockade of Jnk or Syk Signaling Pathways.

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.

JUN Amino-Terminal Kinase 1 Signaling in the Proximal Tubule Causes Cell Death and Acute Renal Failure in Rat and Mouse Models of Renal Ischemia/Reperfusion Injury.

Activation of the JUN amino-terminal kinase (JNK) pathway is prominent in most forms of acute and progressive tubulointerstitial damage, including acute renal ischemia/reperfusion injury (IRI). Two forms of JNK, JNK1 and JNK2, are expressed in the kidney. Systemic administration of pan-JNK inhibitors suppresses renal IRI; however, the contribution of JNK1 versus JNK2, and the specific role of JNK activation in the proximal tubule in IRI, remains unknown. These questions were addressed in rat and mouse models of acute bilateral renal IRI. Administration of the JNK inhibitor, CC-930, substantially reduced the severity of renal failure, tubular damage, and inflammation at 24 hours in a rat IRI model. Additionally, Jnk1-/- mice, but not Jnk2-/- mice, were shown to be significantly protected against acute renal failure, tubular damage, and inflammation in the IRI model. Furthermore, mice with conditional Jnk1 deletion in the proximal tubule also showed considerable protection from IRI-induced renal failure, tubular damage, and inflammation. Finally, primary cultures of Jnk1-/-, but not Jnk2-/-, tubular epithelial cells were protected from oxidant-induced cell death, in association with preventing phosphorylation of proteins (receptor interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase) in the necroptosis pathway. In conclusion, JNK1, but not JNK2, plays a specific role in IRI-induced cell death in the proximal tubule, leading to acute renal failure.

The JNK Signaling Pathway in Renal Fibrosis.

Fibrosis of the glomerular and tubulointerstitial compartments is a common feature of chronic kidney disease leading to end-stage renal failure. This fibrotic process involves a number of pathologic mechanisms, including cell death and inflammation. This review focuses on the role of the c-Jun amino terminal kinase (JNK) signaling pathway in the development of renal fibrosis. The JNK pathway is activated in response to various cellular stresses and plays an important role in cell death and inflammation. Activation of JNK signaling is a common feature in most forms of human kidney injury, evident in both intrinsic glomerular and tubular cells as well as in infiltrating leukocytes. Similar patterns of JNK activation are evident in animal models of acute and chronic renal injury. Administration of JNK inhibitors can protect against acute kidney injury and suppress the development of glomerulosclerosis and tubulointerstitial fibrosis. In particular, JNK activation in tubular epithelial cells may be a pivotal mechanism in determining the outcome of both acute kidney injury and progression of chronic kidney disease. JNK signaling promotes tubular epithelial cell production of pro-inflammatory and pro-fibrotic molecules as well as tubular cell de-differentiation toward a mesenchymal phenotype. However, the role of JNK within renal fibroblasts is less well-characterized. The JNK pathway interacts with other pro-fibrotic pathways, most notable with the TGF-ß/SMAD pathway. JNK activation can augment TGF-ß gene transcription, induce expression of enzymes that activate the latent form of TGF-ß, and JNK directly phosphorylates SMAD3 to enhance transcription of pro-fibrotic molecules. In conclusion, JNK signaling plays an integral role in several key mechanisms operating in renal fibrosis. Targeting of JNK enzymes has therapeutic potential for the treatment of fibrotic kidney diseases.

Early serum creatinine accurately predicts acute kidney injury post cardiac surgery.

BACKGROUND: Acute Kidney Injury (AKI) is a well recognized complication of cardiac surgery. It is associated with significant morbidity and mortality. The aims of our study are twofold; 1. To define the incidence of AKI post cardiac surgery. 2. To identify pre-morbid and operative risk factors for developing AKI and to determine if immediate post operative serum creatinine (IPOsCr) accurately predicts the development of AKI. METHODS: We prospectively studied 196 consecutive patients undergoing elective (on-pump) cardiac surgery. Baseline patient characteristics, including medical co-morbidities, proteinuria, procedural data and kidney function (serum creatinine (sCr) were collected. Internationally standardised criteria for AKI were used (sCr >1.5 times baseline, elevation in sCr >26.4 µmmol/L (0.3 mg/dl). Measurements were collected pre-operatively, within 2 h of surgical completion (IPOsCr) and daily for two days. Logistic regression was used to assess predictive factors for AKI including IPOsCr. Model discrimination was assessed using ROC AUC curves. RESULTS: Forty (20.4%) patients developed AKI postoperatively. Hypertension (OR 2.64, p = 0.02), diabetes (OR 2.25, p = 0.04), proteinuria (OR 2.48, p = 0.02) and a lower baseline eGFR (OR 0.74, p = 0.002) were associated with AKI in univariate analysis. A multivariate logistic model with preoperative and surgical factors (age, gender, eGFR, proteinuria, hypertension, diabetes and type of cardiac surgery) demonstrated moderate discrimination for AKI (ROC AUC 0.76). The addition of IPOsCr improved model discrimination for AKI (AUC 0.82, p = 0.07 versus baseline AUC) and was independently associated with AKI (OR 7.17; 95% CI 1.27-40.32; p = 0.025). CONCLUSIONS: One in 5 patients developed AKI post cardiac surgery. These patients have significantly increased morbidity and mortality. IPOsCr is significantly associated with the development of AKI, providing a cheap readily available prognostic marker.