Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1.
Mineralocorticoids stimulate renal tubular Na(+) reabsorption, enhance salt appetite, increase blood pressure, and favor the development of renal fibrosis. The effects of mineralocorticoids on renal tubular Na(+) reabsorption and salt appetite involve the serum- and glucocorticoid-inducible kinase 1 (SGK1). The kinase is highly expressed in fibrosing tissue. The present experiments thus explored the involvement of SGK1 in renal fibrosis. To this end, SGK1-knockout mice (sgk1 (-/-)) and their wild-type littermates (sgk1 (+/+)) were implanted with desoxycorticosterone acetate (DOCA)-release pellets and offered 1% saline as drinking water for 12 weeks. The treatment led to significant increases in fluid and Na(+) intake and urinary output of fluid and Na(+) in sgk1 (+/+) mice, effects blunted in sgk1 (-/-) mice. Blood pressure increased within the first 7 weeks to a similar extent in both genotypes, but within the next 5 weeks, it increased further only in sgk1 (+/+) mice. Creatinine clearance did not change significantly but albuminuria increased dramatically in sgk1 (+/+) mice, an effect significantly blunted in sgk1 (-/-) mice. Histology after 12 weeks treatment revealed marked glomerular sclerosis and tubulointerstitial damage with interstitial fibrosis and inflammation in kidneys from sgk1 (+/+) mice, but not from sgk1 (-/-) mice. In conclusion, a lack of SGK1 protects against DOCA/high-salt-induced albuminuria and renal fibrosis.
Artunc
Ferruh
F
Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
Amann
Kerstin
K
Nasir
Omaima
O
Friedrich
Björn
B
Sandulache
Diana
D
Jahovic
Nermina
N
Risler
Teut
T
Vallon
Volker
V
Wulff
Peer
P
Kuhl
Dietmar
D
Lang
Florian
F
D000419:Albuminuria / Q000139:chemically induced* / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002118:Calcium / Q000652:urine; D003404:Creatinine / Q000652:urine; D003900:Desoxycorticosterone; D005247:Feeding Behavior; D018390:Gene Targeting; D006400:Hematocrit; D017874:Immediate-Early Proteins / Q000172:deficiency*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000166:cytology / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000201:enzymology* / Q000503:physiopathology; D009929:Organ Size; D011188:Potassium / Q000652:urine; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases
D002118:Calcium; D003404:Creatinine; D003900:Desoxycorticosterone; D017874:Immediate-Early Proteins; D011188:Potassium; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D017673:Sodium Chloride, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases