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Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

Hui Lin, Frank Geurts, Luise Hassler, Daniel Batlle, Katrina M. Mirabito Colafella, Kate M. Denton, Jia L. Zhuo, Xiao C. Li, Nirupama Ramkumar, Masahiro Koizumi, Taiji Matsusaka, Akira Nishiyama, Martin J. Hoogduijn, Ewout J. Hoorn and A.H. Jan Danser
Rhian Touyz, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 462-505; DOI: https://doi.org/10.1124/pharmrev.120.000236

Article Figures & Data

Figures

  • Fig. 1
    Fig. 1

    Overview of all (pro)renin forms, prorenin activation, and the (pro)renin receptor in all its roles.

  • Fig. 2
    Fig. 2

    Proposed role of collecting duct prorenin and the (pro)renin receptor [(P)RR]. Dotted lines show the positive feedback loop of angiotensin II-dependent prorenin and (P)RR synthesis. Prorenin binding to the (P)RR has been linked to water transport, sodium reabsorption, and fibrosis. Independent of prorenin, the (P)RR is involved in lysosomal function and fibrosis. Akt, protein kinase B; AQP2, aquaporin 2; Nox4, NADPH oxidase 4; PKA, proteinase kinase A; SGK1, serine/threonine-protein kinase 1.

  • Fig. 3
    Fig. 3

    Proposed mechanism of renal angiotensin (Ang) II generation and its function. (A) Under normal conditions, a portion of plasma AGT is filtered through the glomeruli and reabsorbed by proximal convoluted tubules (PCTs, S1, and S2 segments) via megalin. Its contribution to renal Ang II generation is marginal. AGT is synthesized in proximal straight tubules (PSTs, S3 segment), but this AGT also makes little contribution to renal Ang II formation, although it may appear in urine. Renal Ang II is probably generated from liver-derived AGT in the capillary lumen or interstitium. (B) In nephrotic syndrome, podocyte injury increases glomerular leakage of plasma AGT. The filtered AGT is reabsorbed by proximal tubules via megalin and thereafter converted to Ang II. The increased renal Ang II content may contribute to sodium retention, possibly by activating Na+/H+ exchanger 3 (NHE3) and the epithelial Na+ channel (ENaC) (Koizumi et al., 2019).

  • Fig. 4
    Fig. 4

    Enzymatic pathways involved in the generation and metabolism of angiotensins. AD, aspartate decarboxylase.

  • Fig. 5
    Fig. 5

    Localization of angiotensin II type 1 receptor (AT1R, largely representing its subtype a, AT1aR) and angiotensin II type 2 receptor (AT2R) in the rat kidney using quantitative in vitro autoradiography and opposing actions of AT1R/AT1aR and AT2R in the kidney. Panel A shows the anatomic localization of AT1R/AT1aR with high levels in the glomerulus (g) and the inner stripe of the outer medulla corresponding to vasa recta bundles, and moderate levels in the proximal convoluted tubules (pct) in the cortex (pct) and renomedullary interstitial cells (RMICs) in the inner stripe of the outer medulla between vasa recta bundles. The inner medulla (IM) expresses a very low level of AT1R/AT1aR. Panel B shows the anatomic localization of AT2R, with low levels in the outer cortex, corresponding to the glomeruli and the proximal tubules, and the inner stripe of the outer medulla, corresponding to vasa recta bundles and RMICs. Again, the IM expresses a very low level of AT2R. Red represents high level (H), whereas dark blue represents background levels (L). Modified from Zhuo et al. (1992, 1994).

  • Fig. 6
    Fig. 6

    Effect of sex on renal angiotensin receptor expression and kidney function and health. Expression of the angiotensin II type 2 receptor (AT2R) and Mas receptor are differentially modulated by sex chromosomes and sex hormones and are influenced by female-specific conditions and diseases. Consequently, in males, the relative renal angiotensin receptor balance is skewed toward the angiotensin II type 1 receptor (AT1R), which enhances vasoconstriction, sodium reabsorption and proinflammatory and profibrotic effects within the kidney. Conversely, adult females have greater expression of the AT2 and Mas receptors than males, which counterbalances the effect of the AT1 receptor and enhances vasodilation, natriuresis and anti-inflammatory and antifibrotic effects within the kidney. In females, various factors such as age, menopause, and complications of pregnancy can lead to a reduction in the renal expression of AT2 and Mas receptors, leading to an increase in blood pressure and sodium retention and adverse effects on kidney health. MasR, Mas receptor.

  • Fig. 7
    Fig. 7

    Scheme showing that extracellular (endocrine and paracrine) angiotensin (Ang) II is taken up via Ang II type 1a receptor (AT1aR)-mediated internalization and then results in Gq/11/phospholipase C (PLC) signaling. Under physiologic conditions (low Ang II), internalized Ang II is sorted to the lysosomal pathway for degradation, whereas AT1a receptors recycle back to the membrane. Alternatively, particular at sustained high extracellular Ang II levels, the Ang II–AT1aR complex may bypass the lysosomal degradation pathway, allowing its transport to mitochondria and nucleus, where Ang II activates AT1aR and/or Ang II type 2 receptor (AT2R) to alter mitochondrial oxidative and glycolysis stress responses. This may in turn alter the expression or activity of Na+/H+ exchanger 3 (NHE3) on the apical membranes, or Na+/K+-ATPase and the Na+/HCO3− cotransporter on the basolateral membranes in the proximal tubules. Thus, activation of the mitochondrial Ang II/AT1aR/O2− signaling will stimulate proximal tubule sodium reabsorption, impair the pressure-natriuresis response, and elevate blood pressure. Conversely, activation of the mitochondrial Ang II/AT2R/NO/cGMP signaling by overexpressing AT2R in the mitochondria will likely inhibit proximal tubule sodium reabsorption, augment the pressure-natriuresis response, and lower blood pressure. Modified from Li et al. (2020, 2021).

  • Fig. 8
    Fig. 8

    Immunohistochemical characterization of human induced pluripotent stem cell-derived kidney organoids. (A) Wilms’ tumor suppressor gene 1 (WT1) staining of glomerular structures; (B) Villin1 staining of proximal tubular structures; (C) E-cadherin staining of distal tubular structures; (D) CD31 staining of endothelial cells; (E) Renin staining, localized around WT1+ area. Organoids were generated as described by Shankar et al. (2021). Scale bar = 50 μm.

  • Fig. 9
    Fig. 9

    Effect of angiotensin (Ang) II type 1 receptor blockade with valsartan, angiotensin-converting enzyme inhibition with captopril, angiotensinogen (AGT) siRNA, or their combination during 4 weeks on the levels of Ang I, Ang II, Ang III, and Ang-(1-7) in blood and kidney of spontaneously hypertensive rats. Modified from Uijl et al. (2019). *P < 0.05 vs. vehicle. LLOQ, lower limit of quantification.

  • Fig. 10
    Fig. 10

    Effect of angiotensin (Ang) II type 1 receptor blockade with losartan, angiotensin-converting enzyme inhibition with captopril, angiotensinogen (AGT) siRNA, or their combination during 4 weeks on the levels of Ang I, Ang II, Ang III, and Ang-(1-7) in blood and kidney of five-sixths nephrectomy rats. Modified from Bovée et al. (2021). *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle. LLOQ, lower limit of quantification.

  • Fig. 11
    Fig. 11

    Proposed mechanism of how renin-angiotensin system (RAS) blockers work, even when not lowering the tissue levels of angiotensin (Ang) II. Normally, Ang II generation occurs in a highly localized manner by angiotensin-converting enzyme (ACE), allowing local Ang II type 1 receptor (AT1R) stimulation. After treatment with an AT1R (ARB) or ACE inhibitor (ACEI), this is no longer possible, although upregulation of ACE and AT1R expression at alternative sites may occur, thus still allowing Ang II formation and AT1R stimulation but in a less efficient (‘diluted’) manner.

  • Fig. 12
    Fig. 12

    Scheme of the biologic actions of angiotensin (Ang) II and Ang-(1-7) and the role of ACE2.

  • Fig. 13
    Fig. 13

    Interactions between prostaglandins and the renin-angiotensin system (RAS) in the kidney. Firstly, in the vasculature, prostaglandin E2 (PGE2) and I2 (PGI2) cause vasodilatation, counteracting the vasoconstriction of angiotensin (Ang) II. Secondly, in the kidney cortex, PGE2 is produced when hypovolemia occurs and subsequently induces renin production by juxtaglomerular cells. Finally, in the kidney medulla, PGE2 counteracts the effects of Ang II on sodium retention.

  • Fig. 14
    Fig. 14

    Effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on the systemic and intrarenal renin-angiotensin system (RAS).

Tables

  • TABLE 1

    (Pro)renin and the (pro)renin receptor [(P)RR] in the collecting duct: synthesis and effects, including effects that involve the soluble s(P)RR

    Synthesis
    (Pro)renin↑ after Ang II (Prieto-Carrasquero et al., 2004)
    ↑ after low sodium (Rohrwasser et al., 1999)
    ↑ after hyperglycemia (Kang et al., 2008)
    (P)RR↑ after Ang II (Gonzalez et al., 2011, 2014b; Wang et al., 2014)
    ↑ after low sodium (Quadri and Siragy, 2014)
    ↑ or = after hyperglycemia (Ichihara et al., 2008; Matavelli et al., 2010)
    Effects (P)RR
    Water transport↑ via Ang II or Ang II–independent (Song et al., 2013; Ramkumar et al., 2015; Lu et al., 2016b; Wang et al., 2016)
    Sodium reabsorption↑ partly via Ang II (Ramkumar et al., 2015, 2016b, 2018; Lu et al., 2016a,b; Quadri and Siragy, 2016)
    Fibrosis↑ Ang II–independent (Reyes-Martinez et al., 2019)
    Urinary acidification↑ (pro)renin-independent (Trepiccione et al., 2016)
    Effects s(P)RR
    Water transport↓ in a polyuria model (Lu et al., 2016b; Wang et al., 2019)
    Sodium reabsorption↑ via ENaC (Wang et al., 2020; Feng et al., 2021)
    Blood pressure↑ during Ang II infusion (Ramkumar et al., 2021)
  • TABLE 2

    Levels of angiotensin metabolites in kidney and blood in various rat strains

    SD(mRen2)27SDSHR(mRen2)27
    n = 6
    mean ± S.E.M.    		n = 8
    mean ± S.E.M.    		n = 6–8
    mean (IQL range)    		n = 8
    mean ± S.D.    		n = 5–8
    mean ± S.E.M.
    Kidney (fmol/g)
    Ang-(1-10)234 ± 3320 ± 2564 (313–907)413 ± 139163 ± 69
    Ang-(1-8)338 ± 33474 ± 40729 (431–1892)431 ± 44388 ± 36
    Ang-(1-7)33 ± 8ND173 (65–279)66 ± 4520 ± 3
    Ang-(1-5)NDND17 (<13–40)16 ± 613 ± 4
    Ang-(2-8)<15ND75 (44–121)<826 ± 3
    Ang-(3-8)NDND<10ND5 ± 0
    Ang-(2-10)37 ± 5NDNDND30 ± 15
    Ang-(1-9)113 ± 19NDNDND42 ± 12
    Blood (fmol/ml)
    Ang-(1-10)100 ± 3578 ± 5141 (103–200)375 ± 196ND
    Ang-(1-8)47 ± 15125 ± 9105 (75–141)36 ± 36ND
    Ang-(1-7)5 ± 213 ± 1<8<7ND
    Ang-(1-5)NDND5 (3–6)2 ± 1ND
    Ang-(2-8)29 ± 8ND4 (<2.5–6)<3ND
    Ang-(3-8)NDND4 (3–6)4 ± 6ND
    Ang-(2-10)34 ± 12NDNDNDND
    Ang-(1-9)<1NDNDNDND

    • IQL, interquartile; m(Ren2)27, transgenic rat overexpressing mouse Ren2 gene; ND, not done; SD, Sprague Dawley.

    • Data are from Campbell et al. (1991, 1995b); Roksnoer et al. (2015); and Uijl et al. (2019, 2021) and have been determined either by radioimmunoassay after high-performance liquid chromatography separation (first two columns) or by using liquid chromatography-tandem mass-spectrometry (last three columns).

  • TABLE 3

    Urinary angiotensinogen in patients with kidney disease

    Chronic Kidney Disease

    • UAGT correlates with ACR (Yamamoto et al., 2007; Kobori et al., 2008; Kim et al., 2011a; Lee et al., 2011; Mills et al., 2012; Zhang et al., 2013; Jeon et al., 2020).

    • Lower eGFR is associated with higher UAGT (Yamamoto et al., 2007; Kobori et al., 2008; Kim et al., 2011a; Mills et al., 2012; Zhang et al., 2013; Jeon et al., 2020).

    • UAGT correlates with intrarenal Ang II or AGT (Yamamoto et al., 2007; Zhang et al., 2013).

    • UAGT correlates with severity of kidney damage on biopsy (Kim et al., 2011a).

    • UAGT is increased compared with healthy controls (Kobori et al., 2008; Mills et al., 2012; Zhang et al., 2013).

    • UAGT predicts effect of (Jeon et al., 2020) and is reduced after ACEI or ARB (Lee et al., 2011).

    Diabetic Kidney Disease

    • UAGT correlates with ACR (Terami et al., 2013; Satirapoj et al., 2014; Park et al., 2015b; Zhuang et al., 2015; Lee et al., 2017; Ba Aqeel et al., 2019).

    • Lower eGFR is associated with higher UAGT (Terami et al., 2013; Satirapoj et al., 2014; Zhuang et al., 2015).

    • Lower eGFR is not associated with higher UAGT (Park et al., 2015b).

    • UAGT correlates with tubular damage markers (Terami et al., 2013).

    • UAGT is higher in DKD compared with controls (Satirapoj et al., 2014) or type 1 diabetes mellitus without DKD (Wysocki et al., 2017a).

    • UAGT is also increased in DKD patients without overt albuminuria (Satirapoj et al., 2014; Zhuang et al., 2015).

    • UAGT is higher in DKD compared with CKD (Park et al., 2015b).

    • UAGT does not predict disease progression after correction for ACR (Lee et al., 2017; Ba Aqeel et al., 2019).

    • UAGT predicts disease progression after correction for ACR and other clinical parameters (Satirapoj et al., 2019).

    IgA Nephropathy

    • UAGT correlated with ACR (Urushihara et al., 2010; Kim et al., 2011b; Konishi et al., 2011; Nishiyama et al., 2011; Jang et al., 2012; Urushihara et al., 2015).

    • Lower eGFR is associated with higher UAGT (Kim et al., 2011b; Jang et al., 2012).

    • No association between eGFR and UAGT (Ohashi et al., 2020).

    • UAGT is higher compared with healthy controls (Urushihara et al., 2010; Kim et al., 2011b; Nishiyama et al., 2011) and other causes of CKD (Kim et al., 2011b).

    • UAGT correlates to disease severity (Konishi et al., 2011; Jang et al., 2012; Urushihara et al., 2015) and Ang II/AGT (Nishiyama et al., 2011; Jang et al., 2012) in kidney biopsies.

    • UAGT decreases after RAS inhibition (Urushihara et al., 2010, 2015; Nishiyama et al., 2011).

    • UAGT predicts eGFR and proteinuria, no correction for ACR (Jang et al., 2012).

    Autosomal Dominant Polycystic Kidney Disease

    • UAGT correlated with ACR (Kocyigit et al., 2013; Kurultak et al., 2014; Salih et al., 2017; Kim et al., 2019; Park et al., 2020).

    • Lower eGFR is associated with higher UAGT (Park et al., 2015a).

    • No association between eGFR and UAGT (Kocyigit et al., 2013; Salih et al., 2017; Park et al., 2020).

    • Positive (Park et al., 2015a) or no correlation (Salih et al., 2017; Park et al., 2020) of UAGT with total kidney volume.

    • UAGT increased compared with healthy controls (Kocyigit et al., 2013; Kurultak et al., 2014) and CKD (Salih et al., 2017; Kim et al., 2019).

    • UAGT predicts disease progression (Park et al., 2020).

    • UAGT correlated to serum potassium (Kim et al., 2019).

    Miscellaneous

    • In patients with nephrotic range proteinuria, UAGT correlates with proteinuria (Jang et al., 2014; Tang et al., 2018).

    • Plasma AGT correlates with UAGT in patients with nephrotic syndrome (Jang et al., 2014).

    • No correlation between ACR and UAGT in minimal change disease (Tang et al., 2018).

    • UAGT is increased in patients with AA amyloidosis compared with healthy controls (Kutlugün et al., 2012).

    • The AGT/ACR ratio differentiates between TIN and IgA nephropathy (Ohashi et al., 2020).

    • ACR, albumin/creatinine ratio; TIN, tubulointerstitial nephritis; UAGT, urinary angiotensinogen.

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Review ArticleReview Article

Kidney Angiotensin in Cardiovascular Disease

Hui Lin, Frank Geurts, Luise Hassler, Daniel Batlle, Katrina M. Mirabito Colafella, Kate M. Denton, Jia L. Zhuo, Xiao C. Li, Nirupama Ramkumar, Masahiro Koizumi, Taiji Matsusaka, Akira Nishiyama, Martin J. Hoogduijn, Ewout J. Hoorn and A.H. Jan Danser
Pharmacological Reviews July 1, 2022, 74 (3) 462-505; DOI: https://doi.org/10.1124/pharmrev.120.000236
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