Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction

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296

Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liverderived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II. CKDs are often progressive and involve cardiovascular diseases. Pharmacological intervention of angiotensin II (AII) is the only currently available therapeutic clinical measure with proven effectiveness in protecting the kidney from progressive loss of renal function in CKD. However, in these conditions, circulating AII is typically not elevated. Of note, AII content in renal tissues is markedly higher than content in the circulation, and it is regulated in a manner distinct from circulating AII. 1-3 These findings have formed the currently prevailing notion that the kidney in and of itself is furnished with a full set of components necessary for de novo AII synthesis. In support of this notion, studies have shown that renal AII is elevated in hypertension and

Section: Discussionmentioning

confidence: 99%

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II

Matsusaka

Niimura

Shimizu

et al. 2012

229

296

“…UUO is associated with increased plasma Ang II that activates renal cells to produce profibrotic factors and ECM, [72][73][74][75][76][77] and TRPC3 has been shown to be activated among others by Ang II. 78,79 Hence, we assessed the role of TRPC3 in Ang II-mediated Ca 2+ entry in renal fibroblasts and found that pyr3 drastically affected Ang II response.…”

Section: Discussionmentioning

confidence: 99%

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Saliba¹,

Karam²,

Smayra

et al. 2015

Transient receptor potential canonical (TRPC) Ca 2+ -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II-and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca 2+ entry in these cells, which was detected by fura-2 Ca 2+ imaging. TRPC3 blockade or Ca 2+ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signalregulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca 2+ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca 2+ -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.

“…[1][2][3][4] These benefits of ACE inhibition and ATR blockade are probably attributed to the suppression of intrarenal angiotensin II concentrations and the changes that follow as a consequence. 4,5 Recent clinical and experimental studies have demonstrated that elevated plasma aldosterone may also contribute to the progression of cardiac and renal disease.…”

mentioning

confidence: 99%

Aldosterone-Stimulated SGK1 Activity Mediates Profibrotic Signaling in the Mesangium

Terada

Kuwana²,

Kobayashi³

et al. 2008

Several recent reports support the hypothesis that aldosterone contributes to the progression of renal injury. Mineralocorticoids increase the expression of serum-and glucocorticoid-inducible protein kinase 1 (SGK1), which is upregulated in several fibrotic diseases. It was hypothesized that SGK1 may mediate the effects of aldosterone on glomerular fibrosis and inflammation. In primary cultures of rat mesangial cells, aldosterone stimulated the expression, phosphorylation, and kinase activity of SGK1, as well as SGK1-dependent NF-B activity. Furthermore, aldosterone augmented the promoter activity and protein expression of intercellular adhesion molecule-1 (ICAM-1), which modulates the inflammatory response, and the profibrotic cytokine connective tissue growth factor (CTGF) in an SGK1-and NF-Bdependent manner. Similar to the in vitro results, uninephrectomized rats that were treated with aldosterone demonstrated increased glomerular expression of SGK1, ICAM-1, and CTGF proteins than untreated rats; these changes were accompanied by hypertension, glomerulosclerosis, and inflammation. In conclusion, these findings suggest that aldosterone stimulates ICAM-1 and CTGF transcription via the activation of SGK1 and NF-B, effects that may contribute to the progression of aldosteroneinduced mesangial fibrosis and inflammation. Accumulating evidence suggests that angiotensinconverting enzyme (ACE) inhibition or angiotensin II receptor (ATR) blockade attenuates the decline in renal function and structural damage in various kidney diseases. 1-4 These benefits of ACE inhibition and ATR blockade are probably attributed to the suppression of intrarenal angiotensin II concentrations and the changes that follow as a consequence. 4,5 Recent clinical and experimental studies have demonstrated that elevated plasma aldosterone may also contribute to the progression of cardiac and renal disease. 6,7 Greene et al. 8 demonstrated a significant suppression of hyperaldosteronism and a marked attenuation of proteinuria, hypertension, and glomerulosclerosis in a remnant kidney model using rats that were treated with enalapril and losartan. Similarly, Rocha et al. 9 demonstrated the renoprotective effects of eplerenone and spironolactone in an aldosterone-stimulated rat model. Chrysostomou and Becker 7 found that the addition of spironolactone to ACE inhibitors markedly reduced the urinary excretion rate of protein in patients with chronic renal failure without exerting hemodynamic effects. All of these studies strongly suggest that aldosterone is involved in the pathogenesis of renal injury.Our group recently revealed that aldosterone stimulates the mitogen-activated protein kinase