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Abstract: SA-PO248

The Novel, Clinical Stage Soluble Guanylate Cyclase Activator BI 685509 Slows the Progression of Diabetic Nephropathy in db/db Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Sharma, Nisha, University of Utah Health, Salt Lake City, Utah, United States
  • Liu, Wenjin, University of Utah Health, Salt Lake City, Utah, United States
  • Tang, Anna, University of Utah Health, Salt Lake City, Utah, United States
  • Pieper, Michael P., Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany
  • Reinhart, Glenn A., Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany
  • Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States

Activation of soluble guanylate cyclase (sGC) to restore cyclic guanosine monophosphate (cGMP) and improve functionality of nitric oxide (NO) pathways impaired by oxidative stress is a potential treatment for chronic and diabetic kidney disease (CKD and DKD). Administration of BI-685509, a novel, orally active small molecule sGC activator has been shown to reduce tubulointerstitial fibrosis in the rat UUO model. This study sought to determine whether administration of BI-685509 could slow the progression of glomerulosclerosis in db/db mouse, a model of type 2 diabetes often characterized by relative NO deficiency.


Five groups of 10 mice including normal control, diabetic db/db mice without treatment but being terminated at 14 weeks and 20 weeks respectively, diabetic db/db mice treated with one of two doses of BI-685509 (30 and 100 mpk/day mixed in mouse diet) from weeks 14 to 20. All mice received uninephrectomy at 8 weeks of age to accelerate the development of kidney disease.


Untreated db/db mice that had obesity, hyperglycemia, and hypertriglyceridemia (TG), developed progressive albuminuria and glomerular mesangial matrix expansion between weeks 14 and 20, linked with increased renal production of fibronectin (FN) and type IV collagen (Col-IV); renal oxidative stress was evident by increased Nox4 expression and urinary malondialdehyde (MDA) secretion. Although body weight was comparable in diabetic groups, BI-685509 at the two doses reduced both blood HbA1c (10.4±1.4%, 9.7±1.9% respectively, vs. 11.8±1.6% of untreated db/db at 20 weeks, P<0.05) and TG levels (41.2±14.9, 22.7±12.6 mg/dL respectively, vs. 64.1±21.6 mg/dL of untreated db/db at weeks, P<0.05). Importantly, high dose of BI-685509 slowed the progression of albuminuria. BI-685509 at both doses markedly retarded the increases in glomerular matrix accumulation similarly (by 33%, P<0.05) seen in db/db mice. However, high dose of BI-685509 markedly reduced the renal FN and Col-IV production and renal oxidative stress markers.


These results suggest that treatment with BI-685509 for 6 weeks slow the progression of diabetic nephropathy in db/db mice via multiple actions and underscores its therapeutic potential in CKD and DKD. Currently, BI-685509 is in Phase II clinical trial to be tested for CKD and DKD.


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