Mitotic activation of Akt signalling pathway in Han:SPRD rats with polycystic kidney disease

The mTOR pathway plays an important role in a number of common renal diseases, including acute kidney injury (AKI), diabetic nephropathy (DN), and polycystic kidney diseases (PKD). The activity of mTOR complex 1 (mTORC1) is necessary for renal regeneration and repair after AKI, and inhibition of mTORC1 by rapamycin has been shown to delay recovery from ischemic AKI in animal studies, and to prolong delayed graft function in humans who have received a kidney transplant. For this reason, administration of rapamycin should be delayed or discontinued in patients with AKI until full recovery of renal function has occurred. On the other hand, inappropriately high mTORC1 activity contributes to the progression of the metabolic syndrome, the development of type 2 diabetes, and the pathogenesis of DN. In addition, chronic hyperactivity of mTORC1, and possibly also mTORC2, contributes to cyst formation and enlargement in a number of forms of PKD. Inhibition of mTOR, using either rapamycin (which inhibits predominantly mTORC1) or “catalytic” inhibitors (which effectively inhibit both mTORC1 and mTORC2), provide exciting possibilities for novel forms of treatment of DN and PKD. In this second part of the review, we will examine the role of mTOR in the pathophysiology of DN and PKD, as well as the potential utility of currently available and newly developed inhibitors of mTOR to slow the progression of DN and/or PKD.

Section: Pkdmentioning

confidence: 92%

Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications

Lieberthal

Levine

2012

“…While the murine jck model of renal cystic disease possesses a mutation in a different gene (Nek8) than either PKD1 or PKD2, the mechanisms responsible for cyst formation in jck are similar to those in ADPKD, including intracellular calcium dysregulation, Wnt signaling, cAMP-activated Ras/Raf/ERK signaling, and the Akt/mammalian target of rapamycin pathway (44,53,55). Importantly, common to all cystic diseases, increased proliferation and apoptosis of cystic epithelia, secretory phenotype, loss of cellular polarity, and dedifferentiation exist in both jck and ADPKD (51).…”

Section: Discussionmentioning

confidence: 99%

A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease

Taylor¹,

Ganti²,

Bukanov³

et al. 2010

“…Two key signaling pathways, cyclic AMP (cAMP)-activated B-Raf/MEK/ERK (20,24,32,50,51) and AKT/mTOR/ S6K/S6 (8,9,26,33,34,37,41,42), have been implicated in renal cyst growth and are associated with PKD progression in humans and animal models. In the polycystic kidney (PCK) rat, an orthologous model of human ARPKD, inhibition of renal cAMP production by treating with a vasopressin V2 receptor antagonist or by increasing water intake to reduce plasma vasopressin decreased cell proliferation and ameliorated cystogenesis with an associated reduction of B-Raf/MEK/ERK activity and led to improved renal function (21,47).…”

mentioning

confidence: 99%

PPAR-γ agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease

Yoshihara

Kurahashi²,

Morita

et al. 2011

In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD.