Abstract 971: Inhibition Of Vascular Bk Channel Activity By Caveolae-mediated Angiotensin II Type I Receptor Signaling In Diabetic Vessels

Angiotensin II (Ang II) type I receptor (ATR 1 ) trafficking into caveolae is essential for Ang II signaling, which is known to be abnormal in diabetic vessels. We have shown that the large conductance Ca 2+ actviated K + (BK) channels are also targeted to caveolae in vascular cells. The potential interaction between Ang II signaling and BK channel function in normal and diabetic vessels is unknown. Using whole-cell patch clamp recordings and molecular biology techniques, we examined the mechanisms through which caveolae targeting facilitates the regulation of BK channels by Ang II signaling. We found that in cultured human coronary arterial smooth muscle cells (CASMC) and in freshly isolated rat CASMC, BK channels, ATR 1 , and Src-family protein tyrosine kinases (Src-PTK) were colocalized and enriched in the low buoyant density, caveolae-rich fractions. 2 μM Ang II inhibited BK channel activity by ∼50% in rat and human CASMC and these effects were completely abolished by 2 μM Losartan (a selective ATR 1 inhibitor), 10 μM PP2 (a selective Src-PTK inhibitor), and by caveolin-1 (cav-1) knockdown using 60 nM siRNA. Similar results were obtained in HEK293 cells coexpressing hSlo, BK-β 1 subunit, ATR 1 , cav-1, and Src-PTK, indicating that inhibition of BK channels by Ang II was mediated through ATR 1 activation of Src-PTK and the integrity of caveolae is critical for Ang II signaling. Culturing human CASMC with high glucose (HG, 22 mM) enhanced Ang II-mediated BK channel inhibition (78.8±16.8% vs. 54.5±15.7% in 5 mM glucose, n=3, p<0.05). Analysis of ATR 1 , Src-PTK, and BK channel distribution by sucrose gradient fractionation and by co-immunoprecipitation with anti-cav-1 antibodies showed that expression of ATR 1 and Src-PTK were up-regulated in human CASMC cultured in HG and in CASMC from streptozotocin-induced diabetic rats. Total BK channel protein in these cells was diminished, but the amount of BK channels co-immunoprecipitated with anti-cav-1 antibody was increased, suggesting increased caveolae targeting of BK channels in diabetes, which leads to enhanced Ang II-mediated BK channel inhibition. These results indicate that Ang II-BK channel interaction is critically dependent upon caveolae targeting under normal conditions and in disease states such as diabetes.

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Angiotensin II stimulates internalization and degradation of arterial myocyte plasma membrane BK channels to induce vasoconstriction

AJP Cell Physiology ◽

10.1152/ajpcell.00127.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. C392-C402 ◽

Cited By ~ 23

Author(s):

M. Dennis Leo ◽

Simon Bulley ◽

John P. Bannister ◽

Korah P. Kuruvilla ◽

Damodaran Narayanan ◽

...

Keyword(s):

Plasma Membrane ◽

Angiotensin Ii ◽

Cerebral Arteries ◽

Bk Channels ◽

Bk Channel ◽

Nitric Oxide Donor ◽

Ang Ii ◽

Functional Responses ◽

Early Endosomes ◽

Arterial Contractility

Arterial smooth muscle cells (myocytes) express large-conductance Ca2+-activated K+ (BK) channel α and auxiliary β1 subunits that modulate arterial contractility. In arterial myocytes, β1 subunits are stored within highly mobile rab11A-positive recycling endosomes. In contrast, BKα subunits are primarily plasma membrane-localized. Trafficking pathways for BKα and whether physiological stimuli that regulate arterial contractility alter BKα localization in arterial myocytes are unclear. Here, using biotinylation, immunofluorescence resonance energy transfer (immunoFRET) microscopy, and RNAi-mediated knockdown, we demonstrate that rab4A-positive early endosomes traffic BKα to the plasma membrane in myocytes of resistance-size cerebral arteries. Angiotensin II (ANG II), a vasoconstrictor, reduced both surface and total BKα, an effect blocked by bisindolylmaleimide-II, concanavalin A, and dynasore, protein kinase C (PKC), internalization, and endocytosis inhibitors, respectively. In contrast, ANG II did not reduce BKα mRNA, and sodium nitroprusside, a nitric oxide donor, did not alter surface BKα protein over the same time course. MG132 and bafilomycin A, proteasomal and lysosomal inhibitors, respectively, also inhibited the ANG II-induced reduction in surface and total BKα, resulting in intracellular BKα accumulation. ANG II-mediated BK channel degradation reduced BK currents in isolated myocytes and functional responses to iberiotoxin, a BK channel blocker, and NS1619, a BK activator, in pressurized (60 mmHg) cerebral arteries. These data indicate that rab4A-positive early endosomes traffic BKα to the plasma membrane in arterial myocytes. We also show that ANG II stimulates PKC-dependent BKα internalization and degradation. These data describe a unique mechanism by which ANG II inhibits arterial myocyte BK currents, by reducing surface channel number, to induce vasoconstriction.

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Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

The Journal of General Physiology ◽

10.1085/jgp.200709913 ◽

2008 ◽

Vol 132 (1) ◽

pp. 13-28 ◽

Cited By ~ 66

Author(s):

Thirumalini Vaithianathan ◽

Anna Bukiya ◽

Jianxi Liu ◽

Penchong Liu ◽

Maria Asuncion-Chin ◽

...

Keyword(s):

Membrane Surface ◽

Acyl Chain ◽

Bk Channels ◽

Bk Channel ◽

Water Soluble ◽

Hek293 Cells ◽

Channel Activity ◽

Smooth Muscle Contractility ◽

Acyl Chain Length ◽

Vascular Myocytes

Large conductance, calcium- and voltage-gated potassium (BK) channels are ubiquitous and critical for neuronal function, immunity, and smooth muscle contractility. BK channels are thought to be regulated by phosphatidylinositol 4,5-bisphosphate (PIP2) only through phospholipase C (PLC)–generated PIP2 metabolites that target Ca2+ stores and protein kinase C and, eventually, the BK channel. Here, we report that PIP2 activates BK channels independently of PIP2 metabolites. PIP2 enhances Ca2+-driven gating and alters both open and closed channel distributions without affecting voltage gating and unitary conductance. Recovery from activation was strongly dependent on PIP2 acyl chain length, with channels exposed to water-soluble diC4 and diC8 showing much faster recovery than those exposed to PIP2 (diC16). The PIP2–channel interaction requires negative charge and the inositol moiety in the phospholipid headgroup, and the sequence RKK in the S6–S7 cytosolic linker of the BK channel-forming (cbv1) subunit. PIP2-induced activation is drastically potentiated by accessory β1 (but not β4) channel subunits. Moreover, PIP2 robustly activates BK channels in vascular myocytes, where β1 subunits are abundantly expressed, but not in skeletal myocytes, where these subunits are barely detectable. These data demonstrate that the final PIP2 effect is determined by channel accessory subunits, and such mechanism is subunit specific. In HEK293 cells, cotransfection of cbv1+β1 and PI4-kinaseIIα robustly activates BK channels, suggesting a role for endogenous PIP2 in modulating channel activity. Indeed, in membrane patches excised from vascular myocytes, BK channel activity runs down and Mg-ATP recovers it, this recovery being abolished by PIP2 antibodies applied to the cytosolic membrane surface. Moreover, in intact arterial myocytes under physiological conditions, PLC inhibition on top of blockade of downstream signaling leads to drastic BK channel activation. Finally, pharmacological treatment that raises PIP2 levels and activates BK channels dilates de-endothelized arteries that regulate cerebral blood flow. These data indicate that endogenous PIP2 directly activates vascular myocyte BK channels to control vascular tone.

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Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase

AJP Cell Physiology ◽

10.1152/ajpcell.00133.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. C846-C853 ◽

Cited By ~ 23

Author(s):

Zhijian Wang ◽

Arohan R. Subramanya ◽

Lisa M. Satlin ◽

Núria M. Pastor-Soler ◽

Marcelo D. Carattino ◽

...

Keyword(s):

Coiled Coil ◽

Bk Channels ◽

Bk Channel ◽

Hek293 Cells ◽

Channel Activity ◽

Distal Nephron ◽

Α Subunit ◽

Low Renin Hypertension ◽

Subunit Expression ◽

Cell Expression

Large-conductance, Ca2+-activated K+ channels, commonly referred to as BK channels, have a major role in flow-induced K+ secretion in the distal nephron. With-no-lysine kinase 4 (WNK4) is a serine-threonine kinase expressed in the distal nephron that inhibits ROMK activity and renal K+ secretion. WNK4 mutations have been described in individuals with familial hyperkalemic hypertension (FHHt), a Mendelian disorder characterized by low-renin hypertension and hyperkalemia. As BK channels also have an important role in renal K+ secretion, we examined whether they are regulated by WNK4 in a manner similar to ROMK. BK channel activity was inhibited in a rabbit intercalated cell line transfected with WNK4 or a WNK4 mutant found in individuals with FHHt. Coexpression of an epitope-tagged BK α-subunit with WNK4 or the WNK4 mutant in HEK293 cells reduced BK α-subunit plasma membrane and whole cell expression. A region within WNK4 encompassing the autoinhibitory domain and a coiled coil domain was required for WNK4 to inhibit BK α-subunit expression. The relative fraction of BK α-subunit that was ubiquitinated was significantly increased in cells expressing WNK4, compared with controls. Our results suggest that WNK4 inhibits BK channel activity, in part, by increasing channel degradation through an ubiquitin-dependent pathway. Based on these results, we propose that WNK4 provides a cellular mechanism for the coordinated regulation of two key secretory K+ channels in the distal nephron, ROMK and BK.

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Large-conductance voltage- and Ca2+-activated K+ channel regulation by protein kinase C in guinea pig urinary bladder smooth muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00325.2013 ◽

2014 ◽

Vol 306 (5) ◽

pp. C460-C470 ◽

Cited By ~ 18

Author(s):

Kiril L. Hristov ◽

Amy C. Smith ◽

Shankar P. Parajuli ◽

John Malysz ◽

Georgi V. Petkov

Keyword(s):

Smooth Muscle ◽

Membrane Potential ◽

Guinea Pig ◽

Bk Channels ◽

Bk Channel ◽

K Channel ◽

Channel Activity ◽

Open Probability ◽

Channel Regulation ◽

Pkc Activation

Large-conductance voltage- and Ca2+-activated K+ (BK) channels are critical regulators of detrusor smooth muscle (DSM) excitability and contractility. PKC modulates the contraction of DSM and BK channel activity in non-DSM cells; however, the cellular mechanism regulating the PKC-BK channel interaction in DSM remains unknown. We provide a novel mechanistic insight into BK channel regulation by PKC in DSM. We used patch-clamp electrophysiology, live-cell Ca2+ imaging, and functional studies of DSM contractility to elucidate BK channel regulation by PKC at cellular and tissue levels. Voltage-clamp experiments showed that pharmacological activation of PKC with PMA inhibited the spontaneous transient BK currents in native freshly isolated guinea pig DSM cells. Current-clamp recordings revealed that PMA significantly depolarized DSM membrane potential and inhibited the spontaneous transient hyperpolarizations in DSM cells. The PMA inhibitory effects on DSM membrane potential were completely abolished by the selective BK channel inhibitor paxilline. Activation of PKC with PMA did not affect the amplitude of the voltage-step-induced whole cell steady-state BK current or the single BK channel open probability (recorded in cell-attached mode) upon inhibition of all major Ca2+ sources for BK channel activation with thapsigargin, ryanodine, and nifedipine. PKC activation with PMA elevated intracellular Ca2+ levels in DSM cells and increased spontaneous phasic and nerve-evoked contractions of DSM isolated strips. Our results support the concept that PKC activation leads to a reduction of BK channel activity in DSM via a Ca2+-dependent mechanism, thus increasing DSM contractility.

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Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/160726 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 24

Author(s):

Shu Li ◽

Lina Wang ◽

Xiuchuan Yan ◽

Qinglan Wang ◽

Yanyan Tao ◽

...

Keyword(s):

Angiotensin Ii ◽

Hepatic Fibrosis ◽

Water Soluble ◽

Salvianolic Acid B ◽

Type I ◽

Ang Ii ◽

Radix Salviae Miltiorrhizae ◽

Fibrotic Liver ◽

Salvianolic Acid

The renin-angiotensin system (RAS) plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B), one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II) signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN-) induced rat fibrotic modelin vivoand Ang-II stimulated hepatic stellate cells (HSCs)in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R) and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I) andα-smooth muscle actin (α-SMA) productionin vitro, reduced the gene expression of transforming growth factor beta (TGF-β), and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation.

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BK channel inhibition by strong extracellular acidification

eLife ◽

10.7554/elife.38060 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 3

Author(s):

Yu Zhou ◽

Xiao-Ming Xia ◽

Christopher J Lingle

Keyword(s):

Bk Channels ◽

Bk Channel ◽

Extracellular Acidification ◽

Channel Inhibition ◽

Wide Range ◽

The Family ◽

Voltage Dependent ◽

Intracellular Organelles ◽

Extracellular Side ◽

Key Residues

Mammalian BK-type voltage- and Ca2+-dependent K+ channels are found in a wide range of cells and intracellular organelles. Among different loci, the composition of the extracellular microenvironment, including pH, may differ substantially. For example, it has been reported that BK channels are expressed in lysosomes with their extracellular side facing the strongly acidified lysosomal lumen (pH ~4.5). Here we show that BK activation is strongly and reversibly inhibited by extracellular H+, with its conductance-voltage relationship shifted by more than +100 mV at pHO 4. Our results reveal that this inhibition is mainly caused by H+ inhibition of BK voltage-sensor (VSD) activation through three acidic residues on the extracellular side of BK VSD. Given that these key residues (D133, D147, D153) are highly conserved among members in the voltage-dependent cation channel superfamily, the mechanism underlying BK inhibition by extracellular acidification might also be applicable to other members in the family.

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Abstract 1476: Angiotensin II Induced Hypertrophic Response And Oxidative Stress Is Attenuated In Mice Lacking The Gene For Tnf-α

Circulation ◽

10.1161/circ.116.suppl_16.ii_304-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Srinivas Sriramula ◽

Nithya Mariappan ◽

Elizabeth McILwain ◽

Joseph Francis

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Collagen Type ◽

Resonance Spectroscopy ◽

Type I ◽

Ang Ii ◽

Hypertrophic Response ◽

Tnf Α ◽

And Oxidative Stress

Tumor necrosis factor-alpha (TNF-α) and angiotensin II (Ang II) play an important role in the pathophysiology of cardiovascular disease in part by inducing the cardiac hypertrophic response and oxidative stress. Recently we demonstrated that angiotensin induced hypertensive response is attenuated in mice lacking the gene for TNF-α. In this study, we examined whether Ang II induced cardiac hypertrophy and increased oxidative stress is mediated through TNF-α. Methods and results: Male TNF-α (−/−) and age matched control (WT) mice were subcutaneously implanted with osmotic minipumps containing Ang II (1 μg/kg/min) or saline for 14 days. Human recombinant TNF-α was injected in one group of TNF-α (−/−) mice (10 μg/kg/day) for 14 days. In WT+Ang mice, a temporal increase in blood pressure was observed during the study as measured by radio telemetry transmitters. At the end of the study, echocardiography revealed an increase in thickness and dimensions of left ventricle (LV) and decreased fractional shortening (%FS) in WT+Ang mice. Real time RT-PCR showed that Ang II- infusion resulted in an increase in heart/bodyweight ratio and of cardiac hypertrophy markers ANP and BNP, and profibrotic genes Collagen Type I, Collagen Type II, and TGF-β in WT mice. Electron Spin resonance spectroscopy revealed an increase in total ROS, superoxide and peroxynitrite in the WT+ANG mice when compared to control WT mice. However, these changes were all attenuated in TNF-α (−/−)+Ang mice. Ang II infusion also increased significantly the mRNA expression of gp91Phox, NOX-1, NOX-4 and AT1R in the LV of WT mice, but not in TNF-α (−/−) mice. Interestingly, injection of TNF-α in the TNF-α (−/−) mice, treated with Ang II resulted in increased cardiac hypertrophy and oxidative stress. Conclusions: Findings from the present study suggest that TNF-α plays an important role in the development of cardiac hypertrophy and oxidative stress in Ang II-induced hypertension.

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Micromolar Ca2+ from sparks activates Ca2+-sensitive K+ channels in rat cerebral artery smooth muscle

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.6.c1769 ◽

2001 ◽

Vol 281 (6) ◽

pp. C1769-C1775 ◽

Cited By ~ 155

Author(s):

Guillermo J. Pérez ◽

Adrian D. Bonev ◽

Mark T. Nelson

Keyword(s):

Smooth Muscle ◽

Laser Scanning ◽

Cerebral Arteries ◽

Bk Channels ◽

Bk Channel ◽

Hill Coefficient ◽

Channel Activity ◽

Acetoxymethyl Ester ◽

Open Probability ◽

Apparent Dissociation Constant

The goal of the present study was to test the hypothesis that local Ca2+ release events (Ca2+ sparks) deliver high local Ca2+concentration to activate nearby Ca2+-sensitive K+ (BK) channels in the cell membrane of arterial smooth muscle cells. Ca2+ sparks and BK channels were examined in isolated myocytes from rat cerebral arteries with laser scanning confocal microscopy and patch-clamp techniques. BK channels had an apparent dissociation constant for Ca2+ of 19 μM and a Hill coefficient of 2.9 at −40 mV. At near-physiological intracellular Ca2+ concentration ([Ca2+]i; 100 nM) and membrane potential (−40 mV), the open probability of a single BK channel was low (1.2 × 10−6). A Ca2+spark increased BK channel activity to 18. Assuming that 1–100% of the BK channels are activated by a single Ca2+ spark, BK channel activity increases 6 × 105-fold to 6 × 103-fold, which corresponds to ∼30 μM to 4 μM spark Ca2+ concentration. 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid acetoxymethyl ester caused the disappearance of all Ca2+sparks while leaving the transient BK currents unchanged. Our results support the idea that Ca2+ spark sites are in close proximity to the BK channels and that local [Ca2+]i reaches micromolar levels to activate BK channels.

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Carvedilol Inhibits Angiotensin II-Induced Proliferation and Contraction in Hepatic Stellate Cells through the RhoA/Rho-Kinase Pathway

BioMed Research International ◽

10.1155/2019/7932046 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Ying Wu ◽

Zhen Li ◽

Sining Wang ◽

Aiyuan Xiu ◽

Chunqing Zhang

Keyword(s):

Cell Cycle ◽

Angiotensin Ii ◽

Liver Fibrosis ◽

Cell Cycle Progression ◽

Rho Kinase ◽

Cell Counting ◽

Type I ◽

Dependent Manner ◽

Ang Ii ◽

Cycle Progression

Aim. Carvedilol is a nonselective beta-blocker used to reduce portal hypertension. This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction. Methods. The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8). Cell cycle progression and apoptosis in HSCs were determined by flow cytometry. A collagen gel assay was used to confirm HSC contraction. The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining. Western blot analyses were performed to detect the expression of collagen I, collagen III, α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others. Results. The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs. Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference. In addition, carvedilol reduced α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice. The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2. Conclusions. The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis. Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway.

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Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension

American Journal of Nephrology ◽

10.1159/000505144 ◽

2020 ◽

Vol 51 (2) ◽

pp. 119-129 ◽

Cited By ~ 3

Author(s):

Giovanna Castoldi ◽

Raffaella Carletti ◽

Silvia Ippolito ◽

Massimiliano Colzani ◽

Francesca Barzaghi ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Diabetic Patients ◽

Type I ◽

Ang Ii ◽

Collagen Expression ◽

Sodium Glucose Cotransporter ◽

Inflammatory Infiltrates

Background: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. Methods: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. Results: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). Conclusions: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in Ang II-dependent hypertension. In Ang II-dependent hypertension, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is independent on the modulation of blood pressure increase.

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