[Abstract unavailable

To determine the role of epidermal growth factor receptor (EGFR) activation in renal functional and structural recovery from acute kidney injury (AKI), we generated mice with a specific EGFR deletion in the renal proximal tubule (EGFRptKO). Ischemia–reperfusion injury markedly activated EGFR in control littermate mice; however, this was inhibited in either the knockout or wild-type mice given erlotinib, a specific EGFR tyrosine kinase inhibitor. Blood urea nitrogen and serum creatinine increased to a comparable level in EGFRptKO and control mice 24 h after reperfusion, but the subsequent rate of renal function recovery was markedly slowed in the knockout mice. Twenty-four hours after reperfusion, both the knockout and the inhibitor-treated mice had a similar degree of histologic renal injury as control mice, but at day 6 there was minimal evidence of injury in the control mice while both EGFRptKO and erlotinib-treated mice still had persistent proximal tubule dilation, epithelial simplification, and cast formation. Additionally, renal cell proliferation was delayed due to decreased ERK and Akt signaling. Thus, our studies provide both genetic and pharmacologic evidence that proximal tubule EGFR activation plays an important role in the recovery phase after acute kidney injury.

Removal of one kidney stimulates synthesis of RNA and protein, with minimal DNA replication, in all nephron segments of the remaining kidney, resulting in cell growth (increase in cell size) with minimal cell proliferation (increase in cell number). In addition to the compensatory renal hypertrophy caused by nephron loss, pathophysiological renal hypertrophy can occur as a consequence of early uncontrolled diabetes. However, the molecular mechanism underlying renal hypertrophy in these conditions remains unclear. In the present study, we report that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following either contralateral nephrectomy or induction of diabetes. In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2.

AKI induces the renoprotective upregulation of survivin expression in kidney epithelial cells, but the underlying mechanisms have not been identified. To determine the role of survivin in renal recovery from AKI, we generated mice with renal proximal tubule-specific deletion of survivin (survivin ptKO ). Renal survivin expression increased substantially in response to ischemia-reperfusion (I/R) injury in control littermates but remained minimal in survivin ptKO mice. Functional and histologic data indicated similar degrees of renal injury in survivin ptKO and control mice 24 hours after reperfusion, but recovery was markedly delayed in survivin ptKO mice. In MCT cells, a mouse renal proximal tubule cell line, ATP depletion by antimycin A treatment upregulated survivin expression through a phospho-STAT3-dependent pathway. In wild-type mice, inhibition of STAT3 kinase diminished I/R-induced upregulation of STAT3 phosphorylation and survivin expression and delayed recovery. Furthermore, I/R injury activated Notch-2 signaling, and a g-secretase inhibitor suppressed I/R-induced Notch-2 signaling, STAT3 phosphorylation, and survivin expression and delayed recovery. In MCT cells, inhibition of g-secretase similarly attenuated antimycin A-induced Notch-2 activation, upregulation of survivin, and phosphorylation of STAT3, but STAT3 kinase inhibition did not prevent Notch-2 activation. Therefore, these data suggest that STAT3 phosphorylation and subsequent upregulation of survivin expression mediated by Notch-2 signaling in renal proximal tubule epithelial cells aid in the functional and structural recovery of the kidney from AKI. AKI is a common clinical condition encountered in both hospital and outpatient settings, and it is an important cause of morbidity and mortality. Approximately 600,000 cases of AKI are reported each year in the United States. 1 Despite significant preclinical and clinical research, supportive therapy remains the only treatment option for AKI patients, and to date, the mortality rates of AKI remain high. 2 It has also become increasingly clear that AKI is associated with the development of CKD. 3,4 Ischemia-reperfusion (I/R) injury is one of the most common causes of AKI in clinical practice, and the underlying pathogenesis involves injury to nephron segments from both the ischemia itself and the resulting inflammatory response. The S3 segment of proximal tubules is most vulnerable to I/R injury. 5 As a result of I/R injury, renal proximal tubule cells exhibit mitochondrial dysfunction, ATP depletion, impaired solute and ion transport, loss of cell polarity, and cytoskeletal disruption, 6 and they may ultimately undergo apoptosis or necrosis.The kidney has a remarkable capacity for regeneration, which is evidenced by the ability to recover renal function after moderate I/R injury.