The Renin-Angiotensin system in Hypertension and Diabetes: from man to rodent and back

Abstract
In addition to the systemic (endocrine) RAS, it is generally believed that the kidney has its own (paracrine) RAS, since it is capable of local angiotensin II synthesis, and all RAS components are expressed locally. Another source of RAS components in the kidney may be endocytotic uptake from the ultrafiltrate. It has been suggested that RAS components in urine reflect the activity of the intrarenal RAS independently from the systemic RAS. This implies that urinary RAS components can be used as a marker for the activity of the intrarenal RAS, or even as renal disease markers. Chapter 2 of this thesis gives an overview of studies on urinary RAS components as markers of the intrarenal RAS. In chapter 4 we conclude that variation in tubular reabsorption is sufficient to explain why urinary renin and albumin excretion do not correlate. In chapter 3 we compare a new renin ELISA with the classical ways of measuring renin, either immunoreactively or enzyme-kinetically. Our data suggest that the ELISA is less sensitive than the other two methods, and makes use of recombinant prorenin as a standard that has not been calibrated against the international standard. In chapters 5 and 6 we review recent studies on renal angiotensin-converting enzyme (ACE), and concluded that the evidence supporting a role for renal ACE in Angiotensin II- or NOS inhibition-induced hypertension is still incomplete.
In chapter 7 we studied the combination of an angiotensin receptor blocker (ARB) with a neprilysin (NEP) inhibitor in hypertensive rats. This combination treatment is referred to as ‘ARNI’. We confirm that ARNI has an additional blood pressure lowering effect compared to ARB alone. However, when the dose of the NEP inhibitor was increased, this effect was annihilated, likely due to an increase in endothelin-1, accompanied by an increase in renal sodium-hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. In chapter 8 we studied the effects of ARNI in diabetic, hypertensive rats. We found that ARNI reduced heart weight, and improved proteinuria and the development of focal segmental glomerulosclerosis more strongly than ARB alone. Blood pressure in ARB- and ARNI-treated animals was equal, which suggests that the observed effects occurred independently of blood pressure. Similar protective effects were found on diabetic retinopathy in these rats in chapter 9.