Changes in Glomerular Perm-Selectivity Induced by Angiotensin II Imply Podocyte Dysfunction and Slit Diaphragm Protein Rearrangement By Ariela Benigni,* Elena Gagliardini,* and Giuseppe Remuzzi* † Molecular mechanisms governing the loss of glomerular membrane perm selectivity during progression of pro- teinuric kidney diseases are so far poorly defined. Discovery of the proteins of the podocyte slit diaphragm, including the nephrin-CD2AP-podocin complex, has represented a major breakthrough in understanding the crucial role of the glomerular epithelial layer in the pathogenesis of proteinuria in human congenital disorders. A number of studies have tried to address the role of nephrin in acquired proteinuric disorders with conflicting results. In human diabetic nephropathy a defect of nephrin gene and protein expression has been consistently reported, which translates in profound changes of filtration slit ultrastructural architecture. The exclusive effect of angiotensin II inhibitors of restoring deficient nephrin expression in proteinuric diseases underlines a close interaction between angiotensin II and podocyte proteins and indicates a fresh way to look at the renoprotective properties of these molecules. © 2004 Elsevier Inc. All rights reserved. E ND-STAGE RENAL FAILURE is increasing worldwide at an alarming rate, fueled by steady rises in prevalence of underlying conditions such as diabetic nephropathy, primary or second- ary glomerulonephritis, HIV nephropathy, and chronic allograft rejection. The consequent human and financial burden is becoming a staggering challenge to public health care systems as a result of the prohibitive costs of renal replacement ther- apy that could become unaffordable even in devel- oped countries. Molecular mechanisms that lead to perturbation or loss of perm selectivity of the glo- merular membrane during progression of protein- uric kidney diseases are so far poorly defined. There is increasing evidence of harmful secondary effects of the excessively filtered proteins across the glomerular capillary barrier on the kidney proximal tubule. The relationship between protein- uria and the rate of renal function decline in most glomerular disorders has been widely described in a number of clinical and experimental studies. Models of heavy proteinuria in rats are character- ized by development of glomerulosclerosis, inter- stitial inflammation, and progressive tubulointer- stitial fibrosis 1-3 Overreabsorption of proteins by the proximal tubules appears to be toxic both for the quantity and the type of proteins that activate inflammatory and fibrogenic factors leading to scarring. 4 Gene expression profiling experiments allowed to identify more than 1000 genes that are upregulated in renal proximal tubules from mice with protein-overload proteinuria. 5 Furthermore, in vitro studies showed that proximal tubular cell cultures exposed to protein overload produced more monocyte chemotactic protein-1 endothe- lin-1, RANTES as a result of nuclear factor kB (NFkB) activation. 6,7 Protein overload proteinuria also induces tubular cell apoptosis that in the long term is responsible for disconnection of tubules from the glomerulus in rats with severe renal in- jury. 8 Apoptosis also occurs in vitro as docu- mented by a dose- and duration-dependent upregu- lation of the Fas-FADD-caspase 8 pathway by proximal tubular cells exposed to excess albumin. 9 Besides proteinuria, 10 angiotensin II (Ang II) has also emerged as a pivotal factor in the patho- genesis of renal injury, 11 to the extent that infusion of Ang II in the rat causes proteinuria, and angio- tensin-converting enzyme inhibitors (ACEi) pre- vent proteinuria by preserving the size-selective restriction to macromolecular probes both in ani- mals and in people. 12,13 Several nonhemodynamics effects of Ang II might also be important in renal disease progression, including mesangial cell pro- liferation, stimulation of both transforming growth factor  and plasminogen activator inhibitor ex- pression, all resulting in increased synthesis of extracellular matrix; activation and infiltration of macrophages and induction of aldosterone produc- tion by adrenal glands. 14 The clinical benefit of preventing renal deterioration by blocking the re- nin–angiotensin system is not entirely explained by antihypertensive action or the antiproteinuric effect From *Mario Negri Institute for Pharmacological Research, Bergamo, and † the Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy. Address reprint requests to Elena Gagliardini, BiolSciD, Mario Negri Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. Email: gagliardini@marionegri.it © 2004 Elsevier Inc. All rights reserved. 0270-9295/04/2402-0006$30.00/0 doi:10.1061/j.semnephrol.2003.11.005 131 Seminars in Nephrology, Vol 24, No 2 (March), 2004: pp 131-140