Add-On Aliskiren Elicits Stronger Renoprotection Than High-Dose Valsartan in Type 2 Diabetic KKAy Mice That Do Not Respond to Low-Dose Valsartan

Abstract

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren.

Calcium Channel Blocker Enhances Beneficial Effects of an Angiotensin II AT1 Receptor Blocker against Cerebrovascular-Renal Injury in type 2 Diabetic Mice

“…The present study showed that these effects were also observed in KK-A y mice and were further exaggerated by high salt intake in type 2 diabetic KK-A y mice. In agreement with our previous studies [41,42], type 2 diabetic KK-A y mice showed renal injury characterized by glomerular podocyte injury leading to albuminuria, glomerular sclerosis and tubulointerstitial fibrosis. Similar to the effects observed on cognitive impairment and BBB disruption, these renal injuries were further aggravated by high salt intake in KK-A y mice.…”

Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy

“…Satriano et al reported that type 1 diabetic rats exhibited renal senescence with increases in p16, p21 and p27 in cortical tubules and that oxidative stress could be one of the mechanisms for proximal tubular senescence (Satriano et al, 2010). We also reported that type 2 diabetic KKAy mice exhibited renal cell senescence with increased p21 expression (Lei et al, 2012). Notably, tubular cells in the kidney of patients with early stage diabetic nephropathy were reported to be senescent (Verzola et al, 2008).…”

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy

“…Sixty male Wistar rats were included in this study and divided randomly into four groups (15 rats each) as follows: group 1: nondiabetic control rats that received drug vehicle (normal saline); group 2: STZ-diabetic control rats that received drug vehicle (normal saline); group 3: diabetic rats treated with fenofibrate (100 mg/kg/day) suspended in 0.5% w/v of carboxymethyl cellulose [30]; group 4: diabetic rats treated with valsartan (15 mg/kg/day) dissolved in normal saline [31]. All groups were treated orally via gavage daily for 12 weeks [30].…”