L-NAME Administration Enhances Diabetic Kidney Disease Development in an STZ/NAD Rat Model

Abstract

One of the most important risk factors for developing chronic kidney disease (CKD) is diabetes. To assess the safety and efficacy of potential drug candidates, reliable animal models that mimic human diseases are crucial. However, a suitable model of diabetic kidney disease (DKD) is currently not available. The aim of this study is to develop a rat model of DKD by combining streptozotocin and nicotinamide (STZ/NAD) with oral N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration. Diabetes was induced in male Wistar rats by intravenous injection of 65 mg/kg STZ, 15 min after intraperitoneal injection of 230 mg/kg NAD. Rats were assigned to different groups receiving L-NAME (100 mg/kg/day) (STZ/NAD/L-NAME) or vehicle (STZ/NAD) for a period of 9 or 12 weeks by daily oral gavage. All rats developed hyperglycemia. Hyperfiltration was observed at the start of the study, whereas increased serum creatinine, albumin-to-creatinine ratio, and evolving hypofiltration were detected at the end of the study. Daily L-NAME administration caused a rapid rise in blood pressure. Histopathological evaluation revealed heterogeneous renal injury patterns, which were most severe in the STZ/NAD/L-NAME rats. L-NAME-induced NO-deficiency in STZ/NAD-induced diabetic rats leads to multiple characteristic features of human DKD and may represent a novel rat model of DKD.

Metformin and Canagliflozin Are Equally Renoprotective in Diabetic Kidney Disease but Have No Synergistic Effect

“…DKD was induced in rats by STZ and NAD injections combined with L-NAME administration, as previously reported [19]. The strength of this model was reconfirmed by the fact that all rats developed severe hyperglycemia, indicating the induction of diabetes.…”

“…The present study aimed to compare the efficacy of metformin, canagliflozin, and a combination of both with quercetin with regards to the development and progression of DKD in rats. DKD was initiated by the induction of diabetes with streptozotocin (STZ) and nicotinamide (NAD), and combined with daily N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration, which further contributes to nephropathy development, as previously demonstrated by our lab [19].…”

Sacubitril/Valsartan Alleviates Cardiac Remodeling and Dysfunction in L-NAME-Induced Hypertension and Hypertensive Heart Disease

“…L-NAME acts as a false substrate for endothelial nitric oxide synthase (eNOS), thus reducing the formation of nitric oxide (NO), resulting in the development of NO-deficient hypertension [14]. Besides the shortage of vasodilative action of NO itself, reduced NO availability in the renal artery is thought to stimulate renin release, followed by angiotensin II (Ang II)-aldosterone axis activation in the circulation [15] and in tissues such as the heart and aorta [16] or kidney [14,17], thus contributing to hypertension development and end-stage organ damage [15]. Nonetheless, our recent investigation revealed that L-NAME-induced hypertension is linked not to heightened, but rather to the normal or reduced activation of the renin-angiotensin II system (RAS) in both serum and LV tissue [18].…”

The Nicotinamide/Streptozotocin Rodent Model of Type 2 Diabetes: Renal Pathophysiology and Redox Imbalance Features

“…The histopathological staining of kidney is also frequently used for the analysis of kidney injury in this NA-STZ animal model. Figure 3 and Figure 4 [ 48 , 49 ] show a typical staining of the kidney tissues by the periodic acid–Schiff and Masson trichrome, respectively. As can be observed from these histochemical stainings, the pathophysiological changes are obvious in the NA-STZ diabetic kidneys.…”

“…Indicated are tubular epithelial cell necrosis (asterisk), thickening of tubular basement membrane (arrow). This figure was reproduced from Corremans et al [ 48 ].…”