Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases

Abstract

In polycystic liver (PLD) and kidney (PKD) diseases, increased cAMP levels trigger hepato-renal cystogenesis. We previously reported that reduction of elevated cAMP by targeting somatostatin receptors (SSTRs) with Octreotide (OCT; a somatostatin analogue that preferentially binds to SSTR2), inhibits cyst growth. We now compare effects of OCT to Pasireotide (PAS; a more potent somatostatin analogue with broader receptor specificity) on: (i) cAMP levels, cell cycle, proliferation and cyst expansion in vitro using cholangiocytes derived from control and PCK rats (a model of autosomal recessive PKD [ARPKD]), healthy human beings and patients with autosomal dominant PKD (ADPKD); and (ii) hepato-renal cystogenesis in vivo in PCK rats and Pkd2WS25/− mice (a model of ADPKD). Expression of SSTRs was assessed in control and cystic cholangiocytes of rodents and human beings. Concentrations of IGF and VEGF (both involved in indirect action of somatostatin analogs), and expression and localization of SSTRs after treatment were evaluated. We showed that PAS was more potent (by 30–45%) than OCT in reducing cAMP and cell proliferation, affecting cell cycle distribution, decreasing growth of cultured cysts in vitro and inhibiting hepato-renal cystogenesis in vivo in PCK rats and Pkd2WS25/− mice. The levels of IGF1 (but not VEGF) were reduced only in response to PAS. Expression of SSTR1 and SSTR2 (but not SSTR3 and SSTR5) was decreased in cystic cholangiocytes compared to control. While both OCT and PAS increased immunoreactivity of SSTR2, only PAS up-regulated SSTR1; neither drug affected cellular localization of SSTRs. Conclusion PAS is more effective than OCT in reducing hepato-renal cystogenesis in rodent models; therefore it might be more beneficial for the treatment of PKD and PLD.

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

“…37, 159 In agreement with the longer half-life and higher affinity to a broader range of SSTRs, the effects of pasireotide are consistently more potent than the effects of octreotide.…”

Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

“…Drugs, such as vasopressin, triptolide, octreotide, and rapamycin, target the pathways involved in these processes (65,(77)(78)(79). Although these signaling modulators have shown a reduction in cystogenesis in clinical trials, they do not improve renal function as much as expected (55,56,58,(80)(81)(82).…”

Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes

“…These novel therapeutic agents block the epidermal growth factor receptor (EGFR), block the vasopressin 2 receptor (V2R), or inhibit the mTOR receptor pathway [2,45,46]. The somatostatin analog octreotide has recently been shown to reduce hepatorenal cystogenesis in rodent models; it might also be beneficial in treating polycystic kidney and liver disease [47]. While some of these drugs are highly effective in animal models [2,45,46,48], others show a potential effect only in kidney disease and not in liver disease (e.g., V2R antagonists) [32,44].…”