Renal denervation has blood pressure–independent protective effects on kidney and heart in a rat model of chronic kidney disease

Abstract

We elucidate the underlying mechanisms of bidirectional cardiorenal interaction, focusing on the sympathetic nerve driving disruption of the local renin-angiotensin system (RAS). A rat model of N(ω)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor) administration was used to induce damage in the heart and kidney, similar to cardiorenal syndrome. L-NAME induced sympathetic nerve-RAS overactivity and cardiorenal injury accompanied by local RAS elevations. These were suppressed by bilateral renal denervation, but not by hydralazine treatment, despite the blood pressure being kept the same between the two groups. Although L-NAME induced angiotensinogen (AGT) protein augmentation in both organs, AGT mRNA decreased in the kidney and increased in the heart in a contradictory manner. Immunostaining for AGT suggested that renal denervation suppressed AGT onsite generation from activated resident macrophages of the heart and circulating AGT excretion from glomeruli of the kidney. We also examined rats treated with L-NAME plus unilateral denervation to confirm direct sympathetic regulation of intrarenal RAS. The levels of urinary AGT and renal angiotensin II content and the degrees of renal injury from denervated kidneys were less than those from contralateral innervated kidneys within the same rats. Thus, renal denervation has blood pressure-independent beneficial effects associated with local RAS inhibition.

Assessment of urinary angiotensinogen as a marker of podocyte injury in proteinuric nephropathies

“…5). This counterintuitive AGT mRNA suppression in the kidney was also observed in a rat model treated with a nitric oxide synthase inhibitor in our previous report (4). This suggests filtration of circulating AGT into the urine enhances reabsorption of AGT at proximal convoluted tubules and leads to suppression of the local generation of AGT at proximal convoluted tubules in a negative feedback mechanism (Fig.…”

“…Rat tissues and paraffin-embedded human renal biopsy specimens were prepared and stained as previously described (4). Briefly, for staining with anti-human AGT, anti-mouse/ rat AGT, anti-desmin, anti-podocin, and anti-albumin antibodies, using paraffin-embedded sections, heat-induced antigen retrieval was performed by autoclaving slides for 20 min in citrate buffer (pH 6.0, Wako Pure Chemical Industries, Osaka, Japan).…”

“…Furthermore, it should be noted that several sites in the kidney have the ability to generate AGT, including proximal tubules (10), podocytes (35), and mesangial cells (30). We previously reported an elevation in the intrarenal RAS and urinary AGT accompanied by AGT expression at injured podocytes, using the nitric oxide inhibition rat model (4). The speculation arose that AGT generated at injured podocytes may be reflected in urinary AGT levels and is therefore useful to predict the activity of podocyte lesions.…”

“…Urinary AGT is elevated and associated with renal prognosis in both patients with various kidney diseases (18,34) and experimental models (4,22). However, the origin of AGT in the urine and the kidney is a matter of debate (25), specifically whether it is derived from circulating AGT (liver derived) (23) or from intrarenal generation (24).…”

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells

“…The increased sympathetic activity contributes to the progression of CKD and to the pathogenesis of hypertension. Several studies have shown that the inhibition of sympathetic excitation, either by renal denervation or pharmacologic agents, attenuates renal damage independent of blood pressure effects in animal models of CKD [2,3,4,5]. The role of renal sympathetic nerves has important clinical implications, and percutaneous catheter-based renal denervation has recently become available to disrupt renal sympathetic nerves.…”