Functional expression of the renin-angiotensin system in human podocytes

Abstract

Experimental and clinical studies impressively demonstrate that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) significantly reduce proteinuria and retard progression of glomerular disease. The underlying intraglomerular mechanisms are not yet fully elucidated. As podocyte injury constitutes a critical step in the pathogenesis of glomerular proteinuria, beneficial effects of ACEI and ARB may partially result from interference with a local renin-angiotensin system (RAS) in podocytes. The knowledge of expression and function of a local RAS in podocytes is limited. In this study, we demonstrate functional expression of key components of the RAS in differentiated human podocytes: podocytes express mRNA for angiotensinogen, renin, ACE type 1, and the AT(1) and AT(2) angiotensin receptor subtypes. In Western blot experiments and immunostainings, expression of the AT(1) and AT(2) receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca(2+) concentration via AT(1) receptors in differentiated human podocytes, whereas it did not increase cAMP. Furthermore, ANG II secretion was detected, which was blocked by neither the ACEI captopril nor the renin inhibitor remikiren nor the chymase inhibitor chymostatin. ANG II secretion of podocytes was not increased by mechanical stress. Finally, ANG II was found to increase staurosporine-induced apoptosis in podocytes. We speculate that ACEI and ARB exert their beneficial effects, in part, by interfering with a local RAS in podocytes. Further experiments are required to identify the underlying molecular mechanism(s) of podocyte protection.

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

“…[25][26][27][28] Mesangial expression of Aogen and ACE has also been documented in renal tissue sections. 19,23 Mesangial cells synthesize Ang II 22,24 and aldosterone, the latter apparently through an Ang II-dependent mechanism.…”

“…19,23 Mesangial cells synthesize Ang II 22,24 and aldosterone, the latter apparently through an Ang II-dependent mechanism. 29 Podocytes also produce Ang II 25,26,28 and aldosterone. 30 Angiotensin type 1 receptors are expressed on mesangial cells 19,24,31 and podocytes 26,28,32 and mineralocorticoid receptors are also expressed by both cell types.…”

“…29 Podocytes also produce Ang II 25,26,28 and aldosterone. 30 Angiotensin type 1 receptors are expressed on mesangial cells 19,24,31 and podocytes 26,28,32 and mineralocorticoid receptors are also expressed by both cell types. 29,33,34 The likely importance of the local glomerular RAAS relates to the pathogenesis of glomeruloscleorsis and the loss of glomerular permselectivity observed in many glomerular diseases.…”

“…83 Thus, in vivo exposure of podocytes to aliskiren is predicted. As podocytes express a functional RAAS, [25][26][27][28] renin inhibition in these cells by aliskiren may Effect of aliskiren and enalapril on blood pressure (a) and albumin excretion (b) in mRen-2 rats. mRen-2 rats were treated with aliskiren or enalapril by subcutaneous osmotic minipumps.…”

“…However, some of the label seen in glomeruli may have reflected aliskiren bound to renin that possibly was present in the mesangial matrix. In addition, as aliskiren can penetrate cultured cardiomyocytes, 98 the drug may have entered mesangial cells and podocytes, both of which express renin 20,[24][25][26] to which aliskiren could bind. Furthermore, the unequivocal evidence for labeled aliskiren in the walls of renal vessels prompts the proposal that this DRI can enter JG cells, and possibly incorporate into forming or formed renin granules.…”