A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat

Abstract

Therapies that restore renal cGMP levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3, and 10 mg/kg/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation, as evidenced by dose-dependent increases in renal cGMP levels.After 15 weeks of treatment, sGC activation resulted in dosedependent decreases in UPE (from 463 6 58 mg/d in vehicle controls to 328 6 55, 348 6 23, 283 6 45, and 108 6 23 mg/d in BI 703704-treated rats at 0.3, 1, 3, and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR.

An integrin antagonist (MK‐0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model

“…It is important to note that the dose of enalapril used in our study is estimated to be roughly 3-10-fold over the clinically relevant dose. This high dose leads to profound hemodynamic effects (Boustany-Kari et al 2016) that are likely the primary mechanism for the immediate drop in proteinuria and the improvement in GFR observed throughout the study. In contrast, ZSF1 rats treated with MK-0429 display late onset reduction in proteinuria 2017 | Vol.…”

“…This high dose leads to profound hemodynamic effects (Boustany‐Kari et al. ) that are likely the primary mechanism for the immediate drop in proteinuria and the improvement in GFR observed throughout the study. In contrast, ZSF1 rats treated with MK‐0429 display late onset reduction in proteinuria suggesting that the underlying mechanism is likely independent of hemodynamics.…”

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy

“…In the same study, high dose angiotensin-converting enzyme (ACE) inhibitor Enalapril normalized blood pressure, prevented renal fibrosis, and virtually eliminated albuminuria. A supramaximal dose of Enalapril was used because several studies in humans have indicated that tissue protection by renin-angiotensin-aldosterone system (RAAS) inhibitors requires doses much higher than needed to normalize blood pressure [11, 41, 42]. Thus, clinical observations seen with Rosiglitazone and Enaplapril are largely recapitulated in obese ZSF1 rats.…”

Reactive Oxygen Comes of Age: Mechanism-Based Therapy of Diabetic End-Organ Damage

“…While the disease progresses, several other renal mediators, such as angiotensin II, AGEs, transforming growth factor (TGF)-b, and protein kinase C (PKC), further increase the activity of NOX enzymes, resulting in a further aggravated renal damage [14]. Impaired cGMP signaling by ROS uncoupling of NOS3 and oxidizing sGC (Figure 1) may further aggravate tubulointerstitial damage and fibrosis [39].…”