Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats

Abstract

Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.

Thiazolidinediones inhibit MDCK cyst growth through disrupting oriented cell division and apicobasal polarity

“…More recent studies have shown a survival benefit in conditional (principal cell) Pkd1 null mice associated with a reduction in systemic blood pressure (but without an effect on cyst formation) and Han:SPRD rats, with a moderate effect on kidney and liver cyst volumes in female Pck rats (2,6,25). Nonetheless, the mechanism of these reported effects remains unclear, with one study reporting no effect on cell proliferation or apoptosis, another reporting reductions in the expression of profibrotic [transforming growth factor (TGF)-␤1] and inflammatory (MCP-1) cytokines and Wnt (␤-catenin) signaling, and finally decreased CFTR expression by cyst epithelia (and thus Cl Ϫ secretion) (2,6,25).…”

Polycystic kidney disease and therapeutic approaches

“…TZDs have been used for the treatment of Type 2 diabetes mellitus (T2DM) because of their good safety during long-term clinical processes for the improvement of renal functions (36). TGF-β1 and MCP-1 expression was suppressed and kidney fibrosis volume and inflammatory cell infiltration were reduced by rosiglitazone treatment in PKD, as was also the case in T2DM disease (33). More recently, the novel PPAR-γ agonist known as alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives, DH9 also had anti-proliferative effects on PKD (37).…”

“…This study was conducted with the expectation that PPAR-γ agonists would attenuate cell proliferation via the checking of cell cycle molecules including PCNA, phosphorylated-Rb, and cyclin D1 and D2 (31). In a recent study, the administration of rosiglitazone was shown to attenuate cyst development and protect renal function via measurements of Blood Urea Nitrogen (BUN) and Creatinine (Cr) in a typical PKD animal model, namely the Han:SPRD rat (33). Additionally, rosiglitazone-treated Cy/+ Han:SPRD rats evidenced longer survival durations than control rats (33).…”

“…In a recent study, the administration of rosiglitazone was shown to attenuate cyst development and protect renal function via measurements of Blood Urea Nitrogen (BUN) and Creatinine (Cr) in a typical PKD animal model, namely the Han:SPRD rat (33). Additionally, rosiglitazone-treated Cy/+ Han:SPRD rats evidenced longer survival durations than control rats (33). In contrast, Raphael et al reported previously that piolglitazone treatment did not result in any reduction of cystogenesis and proliferation, and only affected survival in PC-Pkd1-KO mice (34).…”

Novel Therapies for Polycystic Kidney Disease

“…Small molecule inhibitors of CFTR inhibited the development of PKD in a rodent model [65,66]. PPAR-gamma activators have been shown to inhibit vasopressin mediated chloride transport via CFTR [67] and have been shown to inhibit renal cystic disease in rat models of PKD [68][69][70]. Interestingly, renal cystic disease appears to be less severe in humans who inherited both ADPKD and cystic fibrosis [71,72] further implicating the CFTR chloride channel in the secretion of cyst fluid and contributing to the progression of PKD.…”