Aldosterone-Stimulated SGK1 Activity Mediates Profibrotic Signaling in the Mesangium

Yoshio Terada, Hitoshi Kuwana, Takahiko Kobayashi, Tomokazu Okado, Noriko Suzuki, Takanobu Yoshimoto, Yukio Hirata and Sei Sasaki

Department of Blood Purification and Nephrology, Department of Molecular Endocrinology, Tokyo Medical and Dental University, Tokyo, Japan

Several recent reports support the hypothesis that aldosterone contributes to the progression of renal injury. Mineralocorticoids increase the expression of serum- and glucocorticoid-inducible protein kinase 1 (SGK1), which is upregulated in several fibrotic diseases. It was hypothesized that SGK1 may mediate the effects of aldosterone on glomerular fibrosis and inflammation. In primary cultures of rat mesangial cells, aldosterone stimulated the expression, phosphorylation, and kinase activity of SGK1, as well as SGK1-dependent NF-B activity. Furthermore, aldosterone augmented the promoter activity and protein expression of intercellular adhesion molecule-1 (ICAM-1), which modulates the inflammatory response, and the profibrotic cytokine connective tissue growth factor (CTGF) in an SGK1- and NF-B–dependent manner. Similar to the in vitro results, uninephrectomized rats that were treated with aldosterone demonstrated increased glomerular expression of SGK1, ICAM-1, and CTGF proteins than untreated rats; these changes were accompanied by hypertension, glomerulosclerosis, and inflammation. In conclusion, these findings suggest that aldosterone stimulates ICAM-1 and CTGF transcription via the activation of SGK1 and NF-B, effects that may contribute to the progression of aldosterone-induced mesangial fibrosis and inflammation.

Trombospondina-1 é um ativador endógeno de TGF beta em nefropatia experimental in vivo

Thrombospondin-1 Is an Endogenous Activator of TGF-

in Experimental Diabetic Nephropathy In Vivo

Christoph Daniel,1 Kathrin Schaub,1 Kerstin Amann,2 Jack Lawler,3 and Christian Hugo1

OBJECTIVE—Transforming growth factor-
(TGF-
), the central
cytokine responsible for the development of diabetic nephropathy,
is usually secreted as a latent procytokine complex
that has to be activated before it can bind to its receptors. Recent
studies by our group demonstrated that thrombospondin-1
(TSP-1) is the major activator of latent TGF-
in experimental
glomerulonephritis in the rat, but its role in diabetic nephropathy
in vivo is unknown.

RESEARCH DESIGN AND METHODS—Type 1 diabetes was
induced in wild-type (n 27) and TSP-1–deficient mice (n 36)
via streptozotocin injection, and diabetic nephropathy was investigated
after 7, 9.5, and 20 weeks. Renal histology, TGF-

activation, matrix accumulation, and inflammation were assessed
by immunohistology. Expression of fibronectin and
TGF-
was evaluated using real-time PCR. Furthermore, functional
parameters were examined.

RESULTS—In TSP-1–deficient compared with wild-type mice,
the amount of active TGF-
within glomeruli was significantly
lower, as indicated by staining with specific antibodies against
active TGF-
or the TGF-
signaling molecule phospho-smad2/3
or the typical TGF-
target gene product plasminogen activator
inhibitor-1. In contrast, the amount of glomerular total TGF-

remained unchanged. The development of diabetic nephropathy
was attenuated in TSP-1–deficient mice as demonstrated by a
significant reduction of glomerulosclerosis, glomerular matrix
accumulation, podocyte injury, renal infiltration with inflammatory
cells, and renal functional parameters.

CONCLUSIONS—We conclude that TSP-1 is an important activator
of TGF-
in diabetic nephropathy in vivo. TSP-1–blocking
therapies may be considered a promising future treatment option
for diabetic nephropathy.

Diabetes 56:2982–2989, 2007