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The discussion so far has focused on oxidative stress as a mediator of CVD, however redox signalling has a role in the regulation of kidney function in normal physiology, and there is evidence that oxidative stress plays a role in the pathophysiology of renal impairment, and is an important mediator of progressive CKD.

1.7.1 Redox signalling in renal physiology

Redox signalling plays a role in several aspects of renal function, and as such many of the regulatory components of redox physiology have been identified in the kidney. For example, all three isoforms of NOS are highly expressed, including eNOS which is expressed within the renal vasculature, especially in the glomerulus. Neuronal NOS is expressed by macula densa cells and is involved in tubuloglomerular feedback. Inducible NOS is expressed at high levels even under basal conditions, especially within the interstitium, although its transcription is further enhanced by a number of factors including lipopolysaccharide, hyperglycaemia and hypertension. Several NOX isoforms are also highly expressed, especially NOX-4 which is abundantly produced in the renal cortex.

Infusion of L-NAME into rats with normal renal function causes afferent and efferent arteriolar vasoconstriction, reduced filtration fraction, reduced medullary blood flow and systemic hypertension (Zatz and de Nucci, 1991). Many of the effects of local and systemic RAAS are also mediated through redox signalling. For example, renal afferent arterioles infused with angiotensin II show impaired endothelium mediated dilatation, together with increased NOX mediated generation of O2- and an increase in excretion of peroxidated lipids (Tojo et al., 2002). Angiotensin II infusion also results in upregulation of transcription factors such as NFκB, and cytokines which disrupt normal redox homeostasis. Co-infusion with tempol ameliorates this, and prevents isoprostane excretion (Ding et al., 2015).

There is also evidence of redox signalling involvement in the tubuloglomerular feedback mechanism, by which macular densa cells sense sodium delivery to the distal tubule and regulate glomerular pressure. Accordingly, in response to increased tubular sodium delivery, vasoconstriction is induced primarily in the afferent arteriole, resulting in reduced glomerular pressure and a reduction in single nephron GFR. Macula densa cells show high expression of NOX and neuronal NOS. Microperfusion of L-NAME into macular densa cells enhances tubuloglomerular feedback leading to increased afferent arteriolar vasoconstriction and further reduced glomerular pressure (Welch et al., 2000). This effect tends to occur only during salt delivery, and is absent when tubular sodium is reduced by loop diuretic, suggesting that NO is involved in regulation of tubuloglomerular feedback only during salt loading.

1.7.2 Progression of chronic kidney disease

CKD has a tendency to worsen despite treatment of blood pressure and any other reversible or aetiological factors, and there is evidence that common pathological mechanisms are responsible for this irrespective of the original renal insult. The rate of progression of CKD is extremely variable, relating to clinical parameters such as blood pressure, proteinuria, age, and the presence of various comorbidities. It was shown decades ago, however, that progression of renal impairment shows stronger correlation with degree of tubulointerstitial atrophy and fibrosis than the extent of glomerular disease (Schainuck et al., 1970) . It is thought that tubular atrophy is a final common mechanism by which CKD progresses to ESRD, due to inflammation, infiltration by fibroblasts and mesenchymal to fibroblast transition of resident epithelial cells, ultimately leading to tubulointerstitial scarring and fibrosis (Kuncio et al., 1991).

For example, it was shown using a rat remnant kidney model that progressive renal impairment was more closely associated with dissociation between remaining glomeruli and associated tubules, than with sclerosis of remaining glomeruli (Gandhi et al., 1998). Similarly, in scoring systems used to measure likelihood progression to ESRD in many glomerular diseases including IgA nephropathy, the degree of tubulointerstitial atrophy on kidney biopsy is a significant predictor (Roberts et al., 2009). A number of mechanisms have been suggested by which glomerular damage can be transmitted to the interstitium. Periglomerular tubules may be obliterated by proliferative changes in the glomerulus, whilst leakage of filtrate out of the glomerulus may deposit toxic compounds and proteins around tubular epithelial cells. This in turn can lead to protein reabsorption which causes release of lyosomal enzymes and ROS production. Additionally, injured tubular epithelial cells produce cytokines and transcription factors which recruit inflammatory cells and cause apoptosis of normal glomerular and tubular cells (Chevalier and Forbes, 2008).

Dysfunction of the renal microvasculature is an important component of the tubulointerstitial injury which drives CKD, such that tissue hypoxia and ischaemia is a characteristic feature of CKD. Bohle et al showed peritubular capillary loss in a range of human glomerular and tubulointerstitial diseases, which was associated with the degree of renal impairment (Bohle et al., 1996). The degree of peritubular capillary rarefaction is correlated with degree of tubulointerstitial fibrosis, glomerulosclerosis, and degree of renal impairment (Choi et al.). Microvascular dysfunction may also result from RAAS induced vasoconstriction, and vessel occlusion by inflammatory infiltrate.

1.7.3 Oxidative stress in the progression of chronic kidney

disease

Given the role of redox signalling in vascular function, one may postulate that oxidative stress may have a pathophysiological role in progressive CKD, and this has demonstrated in studies using agents which manipulate redox homeostasis.

For example, Baylis et al showed that chronic supplementation of L-NAME to rats with normal renal function caused proteinuria, renal impairment, and glomerular damage (Baylis et al., 1992). Furthermore, Ding et al showed that tempol ameliorated renal impairment in 5/6 nephrectomised mice, reducing NFκB expression, TGF-β induced fibrosis, and tubular atrophy (Ding et al., 2015). Similarly, the serine protease inhibitor camostat mesilate attenuated renal impairment and tubulointerstitial fibrosis in a mouse model of CKD, partly by reducing expression of NOX components and scavenging hydroxyl radicals (Ueda et al., 2015). Enhanced signalling via epithelial growth factor (EGF) has been shown to be one mechanism by which a number of pro-fibrotic pathways are activated, and EGF inhibition has been shown to ameliorate renal fibrosis and progressive renal impairment. EGF is activated by a number of stimuli including MAP kinases, which are themselves activated by ROS. Rhyu et al implicated ROS activated MAP kinase pathways in the renal fibrosis which occurs in a rat model or allograft nephropathy; at least part of the attenuating effects of ROS inhibition may occur through these mechanisms (Rhyu et al., 2005).