Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension.

Abstract

Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the cytoplasmic domain of the EphA4 receptor has been substituted by enhanced green fluorescent protein (EphA4gf/gf), develop spontaneous hydronephrosis and provide a model for further studies of the disorder. The present study aimed to determine if animals with congenital hydronephrosis develop hypertension and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4gf/gf mice and littermate controls (EphA4+/+) during normal (0.7% NaCl)- and high (4% NaCl)-sodium conditions. Renal excretion, renal plasma flow, and glomerular filtration were studied, and histology and morphology of the kidneys and ureters were performed. EphA4gf/gf mice developed variable degrees of hydronephrosis that correlated with their blood pressure level. In contrast to EphA4+/+, the EphA4gf/gf mice displayed salt-sensitive hypertension, reduced urine concentrating ability, reduced renal plasma flow, and lower glomerular filtration rate. Kidneys from EphA4gf/gf mice showed increased renal injuries, as evidenced by fibrosis, inflammation, and glomerular and tubular changes. In conclusion, congenital hydronephrosis causes hypertension and renal damage, similar to that observed in experimentally induced hydronephrosis. This study further reinforces the supposed causal link between hydronephrosis and later development of hypertension in humans.

• Authors: Johan Sällström, Christiane Peuckert, Xiang Gao, Erik Larsson, Anders Nilsson, Boye L Jensen, Maristela L Onozato, A Erik G Persson, Klas Kullander, Mattias Carlström
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 305 Issue 1 Pg. F71-9 (Jul 01 2013) ISSN: 1522-1466 [Electronic] United States
• PMID: 23637205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sodium Chloride, Dietary
• Receptor, EphA4
• Renin

Topics

• Animals
• Blood Pressure
• Blood Pressure Monitoring, Ambulatory (methods)
• Disease Models, Animal
• Disease Progression
• Female
• Fibrosis
• Glomerular Filtration Rate
• Hydronephrosis (diagnosis, enzymology, genetics, pathology, physiopathology)
• Hypertension (diagnosis, enzymology, genetics, pathology, physiopathology)
• Kidney (blood supply, enzymology, pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptor, EphA4 (genetics, metabolism)
• Renal Plasma Flow
• Renin (blood)
• Signal Transduction
• Sodium Chloride, Dietary (administration & dosage)
• Telemetry
• Ultrasonography, Doppler
• Ureter (enzymology, pathology)