BACKGROUND: Renal enlargement is an early feature of both human and experimental diabetes. Although the precise mechanisms underlying its development are incompletely understood, locally active growth factors have been suggested to have a key role. Having previously documented increased expression of the proproliferative and antiapoptotic growth factor, epidermal growth factor (EGF), in early diabetes-related kidney growth, the present study sought to evaluate its pathogenetic role by blocking its action with a specific inhibitor. METHODS:Sprague-Dawley rats were randomized to receive streptozotocin (diabetic) or buffer (control) and then further randomized to receive either vehicle or the inhibitor of the EGF receptor tyrosine kinase, PKI 166 (100 mg/kg/day) for 2 days and 3 weeks following streptozotocin administration. RESULTS: Experimental diabetes was associated with an increase in kidney weight and tubular epithelial cell proliferation as identified by increased expression of proliferating cell nuclear antigen (PCNA) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. PKI 166 resulted in a 30% reduction in kidney weight in diabetic rats (P < 0.01) and reduced tubular epithelial cell proliferation (P < 0.01). In addition, EGF receptor inhibition also led to a 40% increase in tubular epithelial cell apoptosis at 3 weeks (P < 0.01). Diabetes-associated glomerular enlargement was similarly attenuated by PKI 166, although glomerular hyperfiltration was unaffected. CONCLUSION: These findings suggest that the EGF-EGF receptor (EGFR) axis has a significant role in the development of early diabetes-related kidney growth. The impact of EGFR inhibition on the later development of renal dysfunction, however, remains to be determined.
RCT Entities:
BACKGROUND:Renal enlargement is an early feature of both human and experimental diabetes. Although the precise mechanisms underlying its development are incompletely understood, locally active growth factors have been suggested to have a key role. Having previously documented increased expression of the proproliferative and antiapoptotic growth factor, epidermal growth factor (EGF), in early diabetes-related kidney growth, the present study sought to evaluate its pathogenetic role by blocking its action with a specific inhibitor. METHODS:Sprague-Dawley rats were randomized to receive streptozotocin (diabetic) or buffer (control) and then further randomized to receive either vehicle or the inhibitor of the EGF receptor tyrosine kinase, PKI 166 (100 mg/kg/day) for 2 days and 3 weeks following streptozotocin administration. RESULTS: Experimental diabetes was associated with an increase in kidney weight and tubular epithelial cell proliferation as identified by increased expression of proliferating cell nuclear antigen (PCNA) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. PKI 166 resulted in a 30% reduction in kidney weight in diabeticrats (P < 0.01) and reduced tubular epithelial cell proliferation (P < 0.01). In addition, EGF receptor inhibition also led to a 40% increase in tubular epithelial cell apoptosis at 3 weeks (P < 0.01). Diabetes-associated glomerular enlargement was similarly attenuated by PKI 166, although glomerular hyperfiltration was unaffected. CONCLUSION: These findings suggest that the EGF-EGF receptor (EGFR) axis has a significant role in the development of early diabetes-related kidney growth. The impact of EGFR inhibition on the later development of renal dysfunction, however, remains to be determined.
Authors: Renzhong Li; Lalita Uttarwar; Bo Gao; Martine Charbonneau; Yixuan Shi; John S D Chan; Claire M Dubois; Joan C Krepinsky Journal: J Biol Chem Date: 2015-07-14 Impact factor: 5.157
Authors: Jennifer Sjaarda; Hertzel C Gerstein; Salim Yusuf; Darin Treleaven; Michael Walsh; Johannes F E Mann; Sibylle Hess; Guillaume Paré Journal: J Am Soc Nephrol Date: 2018-03-06 Impact factor: 10.121
Authors: Steven J Forrester; Tatsuo Kawai; Shannon O'Brien; Walter Thomas; Raymond C Harris; Satoru Eguchi Journal: Annu Rev Pharmacol Toxicol Date: 2015-11-09 Impact factor: 13.820