Precocious activation of genes of the renin-angiotensin system and the fibrogenic cascade in IgA glomerulonephritis

Background. The renin-angiotensin system (RAS) seems to play a pivotal role in progression of immunoglobulin A (IgA) nephropathy (IgAN). Accordingly, in patients with IgAN a relationship between the RAS and the fibrogenic cascade triggered by transforming growth factor-beta1 (TGF-beta1) should be observed. This study was carried out to obtain deeper insight into the regulation of RAS and the interaction with TGF-beta1 in the diseased kidney. Methods. Twenty renal biopsies from IgAN patients and five from renal cancer patients (controls) were analyzed in both microdissected glomerular and tubulointerstitial compartments by reverse transcription-polymerase chain reaction (RTPCR). All patients had normal renal function. The expression of the following genes was determined: angiotensinogen (Agtg), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type I and type II (AT1 and AT2 receptors), TGF-beta1, collagen IV (Coll IV), alpha-smooth muscle actin (alpha-SMA). Quantitative data were confirmed for TGF-beta1 and ACE genes by real-time PCR. Results. RAS genes were overexpressed in IgAN patients vs. control subjects. There was no difference between glomerular and tubulointerstitial RAS gene expression levels. On the contrary, the overactivation of fibrogenic cascade genes (TGF-beta1, Coll TV, alpha-SMA) in the tubulointerstitium was observed (TGF-beta1, glomerular 0.14 +/- 0.10 SD; tubulointerstial 0.34 +/- 0.20; P = 0.000) (alpha-SMA, glomerular 0.08 +/- 0.07; tubulointerstitial 0.35 +/- 0.19; P = 0.000) (Coll IV, glomerular 0.12 +/- 0.11; tubulointerstitial 0.22 +/- 0.10; P = 0.03). This fibrogenic cascade seems to be triggered by RAS as indicated by statistically significant correlations between the expression of their respective genes. A direct relationship between the putative Ang II activity and the expression of AT receptor genes was found in the tubulointerstitium, whereas in the glomeruli this relationship was negative. In the interstitium, statistically significant positive relationships emerged between interstitial infiltrates and the gene expression of Agtg, AT1 receptor, Coll IV, and TGF-beta1. Conclusion. This study demonstrates that a tight regulation of the intrarenal RAS exists in IgAN and that it follows the general rules disclosed in animal models. Moreover, the RAS seems to be activated early in the diseased kidney and it appears that such activation drives inflammation and a parallel stimulation of the TGF-beta fibrogenic loop, particularly at the tubulointerstitial level.