The renin-angiotensin system, adrenomedullins and urotensin II in the kidney: Possible renoprotection via the kidney peptide systems

The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney. The classical example is the renin-angiotensin system (RAS). Angiotensin II plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation, and reactive oxygen-generating activity. A renin inhibitor, aliskiren, has recently been shown to be a clinically effective drug to reduce proteinuria in patients with diabetic nephropathy. (Pro)renin receptor, a specific receptor for renin and prorenin, was newly identified as a member of the RAS. When bound to prorenin, (pro)renin receptor activates the angiotensin I-generating activity of prorenin in the absence of cleavage of the prosegment, and directly stimulates the pathway of mitogen-activated protein kinase independently from the RAS. The kidney peptides that antagonize the intrarenal RAS may have renoprotective actions. Adrenomedullins, potent vasodilator peptides, have been shown to have renoprotective actions. On the other hand, urotensin II, a potent vasoconstrictor peptide, may promote the renal dysfunction in chronic kidney disease together with the renal RAS. Thus, in addition to the renin inhibitor and (pro)renin receptor, adrenomedullins and urotensin II may be novel targets to develop therapeutic strategies against chronic kidney disease.