PT  - JOURNAL ARTICLE
AU  - Castañeda, Tamara R.
AU  - Méndez, María
AU  - Davison, Ian
AU  - Elvert, Ralf
AU  - Schwahn, Uwe
AU  - Boldina, Galina
AU  - Rocher, Corinne
AU  - Scherer, Petra
AU  - Singh, Kuldeep
AU  - Bangari, Dinesh
AU  - Falkenhan, Mechthilde
AU  - Kannt, Aimo
AU  - Konkar, Anish
AU  - Larsen, Philip J.
AU  - Arbeeny, Cynthia
AU  - Dhal, Pradeep K.
AU  - Hübschle, Thomas
TI  - <strong>The novel phosphate and bile acid sequestrant polymer SAR442357 delays disease progression in a rat model of diabetic nephropathy</strong>
AID  - 10.1124/jpet.120.000285
DP  - 2020 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2020-000285
4099  - http://jpet.aspetjournals.org/content/early/2020/11/20/jpet.120.000285.short
4100  - http://jpet.aspetjournals.org/content/early/2020/11/20/jpet.120.000285.full
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.