RT Journal Article
SR Electronic
T1 <strong>The novel phosphate and bile acid sequestrant polymer SAR442357 delays disease progression in a rat model of diabetic nephropathy</strong>
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2020-000285
DO 10.1124/jpet.120.000285
A1 Castañeda, Tamara R.
A1 Méndez, María
A1 Davison, Ian
A1 Elvert, Ralf
A1 Schwahn, Uwe
A1 Boldina, Galina
A1 Rocher, Corinne
A1 Scherer, Petra
A1 Singh, Kuldeep
A1 Bangari, Dinesh
A1 Falkenhan, Mechthilde
A1 Kannt, Aimo
A1 Konkar, Anish
A1 Larsen, Philip J.
A1 Arbeeny, Cynthia
A1 Dhal, Pradeep K.
A1 Hübschle, Thomas
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/11/20/jpet.120.000285.abstract
AB As a gut-restricted non-absorbed therapy, polymeric bile acid sequestrants (BAS) play an important role in managing hyperlipidemia and hyperglycemia. Similarly, non-absorbable sequestrants of dietary phosphate have been used for the management of hyperphosphatemia in end stage renal disease. To evaluate the potential utility of such polymer sequestrants to treat type 2 diabetes (T2D) and its associated renal and cardiovascular complications, we synthesized a novel polymeric sequestrant, SAR442357 possessing optimized bile acid (BA) and phosphate sequestration characteristics. Long-term treatment of T2D obese ZSF1 rats with SAR442357 resulted in enhanced sequestration of BAs and phosphate in the gut, improved glycemic control, lowering plasma cholesterol and triglycerides and attenuated diabetic kidney disease (DKD) progression. In comparison, colesevelam, a BAS with poor phosphate binding property did not prevent DKD progression, while losartan, an angiotensin II receptor blocker that is widely used to treat DKD, showed no effect on hyperglycemia. Analysis of hepatic gene expression levels of the animals treated with SAR442357 revealed upregulation of genes responsible for the biosynthesis of cholesterol and BAs, providing clear evidence of target engagement and mode of action of the new sequestrant. Additional hepatic gene expression pathway changes were indicative that there was interruption of the enterohepatic BA cycle. Histopathological analysis of ZSF1 rat kidneys treated with SAR442357 further supported its nephroprotective properties. Collectively, these findings reveal the pharmacological benefit of simultaneous sequestration of BAs and phosphate in treating T2D and its associated comorbidities and cardiovascular complications. Significance Statement A new non-absorbed polymeric sequestrant with optimum phosphate and bile salt sequestration properties was developed as a treatment option for DKD. The new polymeric sequestrant offered combined pharmacological benefits including glucose regulation, lipid lowering and attenuation of DKD progression in a single therapeutic agent.