Extracellular Signal-Regulated Kinase Mediates Renal Regeneration in Rats with Myoglobinuric Acute Renal Injury

Ishizuka, Shino; Yano, Tomohiro; Hagiwara, Kiyokazu; Sone, Masayoshi; Nihei, Hiroshi; Ozasa, Hisashi; Horikawa, Saburo

doi:10.1006/bbrc.1998.9902

Cited by 28 publications

(21 citation statements)

References 24 publications

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“…40 In the kidney, the preponderance of evidence suggests that ERK 1/2 activation protects against oxidant, hypoxic, and ATP depletion-mediated injury of renal epithelial cells in vitro 41,42 as well as oxidant and ischemia-reperfusion injury in vivo. 16,43 Although GFR was not measured, biochemical ERK inhibition promoted the retention of focal adhesions and preserved the actin cytoskeletal network in a single study of renal ischemia. 44 In contrast to ischemia/reperfusion models, ERK inhibition (versus activation) protects against cis-platinum-induced AKI, partly by its effect on apoptosis inhibition 45 and partly by modulating renal epithelial cell cilia.…”

Section: Discussionmentioning

confidence: 99%

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Gall

Wang

Bonegio

et al. 2015

Journal of the American Society of Nephrology

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Proximal tubule (PT) cells are critical targets of acute ischemic injury. Elimination of the mitochondrial fusion protein mitofusin 2 (Mfn2) sensitizes PT cells to apoptosis in vitro. However, the role of PT Mfn2 in ischemic AKI in vivo is unknown. To test its role, we evaluated the effects of conditional KO of PT Mfn2 (cKO-PT-Mfn2) on animal survival after transient bilateral renal ischemia associated with severe AKI. Fortyeight hours after ischemia, 28% of control mice survived compared with 86% of cKO-PT-Mfn2 animals (P,0.001 versus control). Although no significant differences in histologic injury score, apoptosis, or necrosis were detected between genotypes, cKO-PT-Mfn2 kidneys exhibited a 3.5-fold increase in cell proliferation restricted to the intrarenal region with Mfn2 deletion. To identify the signals responsible for increased proliferation, primary PT cells with Mfn2 deficiency were subjected to stress by ATP depletion in vitro. Compared with normal Mfn2 expression, Mfn2 deficiency significantly increased PT cell proliferation and persistently activated extracellular signal-regulated kinase 1/2 (ERK1/2) during recovery from stress. Furthermore, stress and Mfn2 deficiency decreased the interaction between Mfn2 and Ras detected by immunoprecipitation, and purified Mfn2 dose-dependently decreased Ras activity in a cell-free assay. Ischemia in vivo also reduced the Mfn2-RAS interaction and increased both RAS and p-ERK1/2 activity in the renal cortical homogenates of cKO-PT-Mfn2 mice. Our results suggest that, in contrast to its proapoptotic effects in vitro, selective PT Mfn2 deficiency accelerates recovery of renal function and enhances animal survival after ischemic AKI in vivo, partly by increasing Ras-ERK-mediated cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Gall

Wang

Bonegio

et al. 2015

Journal of the American Society of Nephrology

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“…It is well-established that MAPKs, including JNK and ERK1/2, regulate cell proliferation, migration, and differentiation (15,18,21,36,63,72,86,102,120), processes important for salivary gland morphogenesis (60,70) and regeneration of a wide variety of tissues (19,24,50,53,54,56,65,71,80,100,105,107,111,122,124). The P2Y 2 R-mediated activation of ERK1/2 has been reported in HSG cells (94), corneal epithelial cells (13), and human coronary artery endothelial cells (HCAEC) (29).…”

Section: Discussionmentioning

confidence: 99%

P2Y₂ nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells

El-Sayed

Camden

Woods

et al. 2014

American Journal of Physiology-Cell Physiology

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El-Sayed FG, Camden JM, Woods LT, Khalafalla MG, Petris MJ, Erb L, Weisman GA. P2Y2 nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells. Am J Physiol Cell Physiol 307: C83-C96, 2014. First published April 24, 2014 doi:10.1152/ajpcell.00380.2013.-Hyposalivation resulting from salivary gland dysfunction leads to poor oral health and greatly reduces the quality of life of patients. Current treatments for hyposalivation are limited. However, regenerative medicine to replace dysfunctional salivary glands represents a revolutionary approach. The ability of dispersed salivary epithelial cells or salivary gland-derived progenitor cells to self-organize into acinarlike spheres or branching structures that mimic the native tissue holds promise for cell-based reconstitution of a functional salivary gland. However, the mechanisms involved in salivary epithelial cell aggregation and tissue reconstitution are not fully understood. This study investigated the role of the P2Y2 nucleotide receptor (P2Y2R), a G protein-coupled receptor that is upregulated following salivary gland damage and disease, in salivary gland reconstitution. In vitro results with the rat parotid acinar Par-C10 cell line indicate that P2Y2R activation with the selective agonist UTP enhances the self-organization of dispersed salivary epithelial cells into acinar-like spheres.Other results indicate that the P2Y2R-mediated response is dependent on epidermal growth factor receptor activation via the metalloproteases ADAM10/ADAM17 or the ␣5␤1 integrin/Cdc42 signaling pathway, which leads to activation of the MAPKs JNK and ERK1/2. Ex vivo data using primary submandibular gland cells from wild-type and P2Y2R

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“…Intramuscular injection of hypertonic glycerol to Table 2 The plasma activity ALT (U/l), AST (U/l), LDH (U/l), CK (U/l), Na (mEq/l), K (mEq/l) and Ca (mEq/l) for each group rats is a widely used model for experimental myoglobinuric ARF (Shah and Walker 1988). This model is regarded as a mimic of the type of ARF that develops in human (Ishizuka et al 1999). Injection of intramuscular glycerol produces myolysis, hemolysis and hypovolemia.…”

Section: Discussionmentioning

confidence: 99%

Preventive effects of hyperbaric oxygen treatment on glycerol-induced myoglobinuric acute renal failure in rats

et al. 2012

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Myoglobinuric acute renal failure (ARF) is a uremic syndrome caused by traumatic or non-traumatic skeletal muscle breakdown and intracellular elements that are released into the bloodstream. We hypothesized that hyperbaric oxygen (HBO) therapy could be beneficial in the treatment of myoglobinuric ARF caused by rhabdomyolysis. A total of 32 rats were used in the study. The rats were divided into four groups: control, control+hyperbaric oxygen (control+HBO), ARF, and ARF+hyperbaric oxygen (ARF+HBO). Glycerol (8 ml/kg) was injected into the hind legs of each of the rats in ARF and ARF+HBO groups. 2.5 atmospheric absolute HBO was applied to the rats in the control+HBO and ARF+HBO groups for 90 min on two consecutive days. Plasma urea, creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, creatinine kinase and urine creatinine and sodium were examined. Creatinine clearance and fractional sodium excretion could then be calculated. Superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) levels were assessed in renal tissue. Tissue samples were evaluated by Hematoxylin-eosin, PCNA and TUNEL staining histopathologically. MDA levels were found to be significantly decreased whereas SOD and CAT were twofold higher in the ARF+HBO group compared to the ARF group. Renal function tests were ameliorated by HBO therapy. Semiquantitative evaluation of histopathological findings indicated that necrosis and cast formation was decreased by HBO therapy and TUNEL staining showed that apoptosis was inhibited. PCNA staining showed that HBO therapy did not increase regeneration. Ultimately, we conclude that, in accordance with our hypothesis, HBO could be beneficial in the treatment of myoglobinuric ARF.

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Extracellular Signal-Regulated Kinase Mediates Renal Regeneration in Rats with Myoglobinuric Acute Renal Injury

Cited by 28 publications

References 24 publications

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

P2Y₂ nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells

Preventive effects of hyperbaric oxygen treatment on glycerol-induced myoglobinuric acute renal failure in rats

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