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Table 2 Clinical studies of the anti-CKD effects of herbal medicines

Extract type or plant part Study design Study model Results References

Abelmoschus manihot (HKC)

Salvia miltiorrhiza

Berberine • 0.1g, 3 times/day for 2

Berberine • 0.4g, 3 times/day over 6

Zingiber ofcinale

Vitis vinifera • V. vinifera seed extract

Curcuma longa • C. longa containing 95%

Curcumin • Curcumin (1g/day) over 12

Curcumin • Curcumin (320mg/day)

• 2.5g 3 times a day Prospective, open-label, multicenter,

• 50mg losartan daily for 24 weeks

• 2.5g 3 times a day Randomized, non-inferiority,

• 100mg losartan daily for 48 weeks

• Sulfotanshinone IIA+Western standard treatment

• Western standard treatment

• Sodium tanshinone IIA sulfonate injection+ARBs

• ARB monotherapy

years+standard medication

• Standard medication

months+standard medication

• Standard medication

• Z. ofcinale (1000mg/day) over 10 weeks

• Placebo

(2100mg/day) for 6 months

• Placebo

curcumin (2.5g, 3 times per week) over 12 weeks

• Placebo

continuous weeks

• Placebo No signicant changes in hs-CRP,

administered over 8 weeks

• Placebo

randomized, controlled clinical trial on biopsy-proven primary glomerular disease patients

double-blind, multicenter clinical trial on IgAN patients

Meta-analysis of 21 clinical studies involving 1857 patients with CKD

Meta-analysis of 16 clinical studies involving 1696 patients with hypertensive nephropathy

Randomized, controlled clinical trial evaluating hypertensive and type 2 diabetes mellitus patients

Controlled, randomized clinical trial investigating type 2 diabetes mellitus patients

Randomized, placebo-controlled, double-blind clinical trial on patients on peritoneal dialysis

Randomized, placebo-controlled, double-blind clinical trial determining chronic kidney disease patients

Randomized, placebo-controlled, double-blind clinical trial on patients undergoing hemodialysis

Double-blind, randomized, , placebocontrolled clinical trial on patients undergoing hemodialysis

Randomized, placebo-controlled, double-blind clinical trial on non-diabetic or diabetic proteinuric CKD

↓ 24-h proteinuria greater than losartan potassium

↓ 24-h proteinuria similar to losartan potassium

No signicant changes in eGFR

↓ BUN, Scr, urinary protein level over 24 h

↓ Microalbuminuria, β2-macroglobulin, and cystatin C

↑ GFR levels ↓ 24-h urinary protein, Scr,

cystatin-C ↓ Urinary immunoglobulin G and

transferrin

↓ SBP and DBP ↑ GFR level ↓ Scr, urine albumin/Cr

↓ Osteopontin and KIM-1 ↓ VCAM-1 and CRP ↓ MDA level ↑ SOD, GSH-Px, and TAC

activities

↓ BUN, urine albumin/Cr ratio

↓ hs-CRP and cystatin C ↑ eGFR level ↓ Serum fasting glucose

↓ Urinary protein

↓ MDA, protein carbonylation,

H2O

↓ CRP levels ↑ GFR, CAT, GPx, and SOD

activity

↓ NF-kB mRNA expression

↓ hs-CRP level ↑ CAT, GPx activities

MDA levels, and GR activity ↓ MDA level in non-diabetic

patients ↑ Anti-oxidant markers in diabetic

patients No signicant differences in the

urinary protein, eGFR, and Nrf-2 activation

V. BaradaranRahimi and V. R. Askari

[9]

[10]

[23]

[24]

[35]

[36]

[50]

[72]

[82]

[83]

[84]

Role ofHerbal Medicines fortheTreatment ofChronic Kidney Disease

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(continued)

Table 2

Extract type or plant part Study design Study model Results References

Curcumin • Curcumin (500mg twice a

Curcumin • Curcumin Meta-analysis of 5 clinical studies

Curcumin • Curcumin Meta-analysis of 10 clinical studies

Curcumin • Curcumin Meta-analysis of nine clinical studies

Nigella sativa oil

Nigella sativa • Nigella sativa Meta-analysis of 19 clinical studies

Huangkui capsule (HKC), IgA nephropathy (IgAN), blood urine nitrogen (BUN), systolic blood pressure (SBP), serum creatinine (Scr), glomerular ltration rate (GFR), chronic kidney disease (CKD), and diastolic blood pressure (DBP), angiotensin receptor blockers (ARBs), kidney-injurymolecule (KIM-1), malondialdehyde (MDA), superoxide dismutase (SOD), vascular cell adhesion molecule-1 (VCAM-1), glutathione (GSH), estimated glomerular ltration rate (eGFR), high-sensitive C-reactive protein (hs-CRP)

day) over 6 weeks

• Placebo

• Placebo No signicant changes in BUN,

• Placebo

• 2.5mL, taken orally, once daily over 12 weeks

• Control

• Placebo

Randomized, double-blind, placebocontrolled trial on CKD patients

involving 290 patients with diabetic kidney disease

involving 523 CKD patients

on CKD patients Prospective, randomized, and

open-labeled clinical study on patients with Stages 3–4 of CKD

involving 1295 participants

↓ MDA, MCP-1, IL-4, and IFN-γ levels

↓ Scr, total cholesterol, SBP, and fasting blood glucose

urinary protein, triglyceride, and diastolic blood pressure levels

No signicant differences in IL-6, TNF-α, and hs-CRP levels

↓ Total cholesterol and TNF-α levels

↓ Blood urea, Scr, and 24-h urinary protein

↑ Total urine volume over 24h and GFR

↓ ALP and BUN levels

301

[85]

[86]

[87]

[88]

[96]

[97]

2 Abelmoschus manihot L.

Abelmoschus manihot (A. manihot), an annual owering herb, belongs to Malvaceae. It is widely found in eastern European countries, northern Australia, and Asian countries, such as Indonesia, India, Korea, and China [1]. A. manihot has been extensively administered in China as folk medicine, especially for treating CKD. Additionally, the Huangkui capsule (HKC) is a Chinese-approved drug containing the ethanolic extract of A. manihot owers and is prescribed for treating kidney disorders [2].

2.1 Animal Studies

An experiment conducted by Ge etal. determined the effect of HKC in diabetic nephropathy (DN) caused by unilateral nephrectomy and intraperitoneal injection of streptozotocin in Sprague–Dawley rats. They supported that HKC signicantly improved the formation of glomerulosclerosis brosis and mitigated transforming growth factor-β (TGF-β) and collagen type IV expression in the renal tissue of DN rats. It also propagated the peroxisome proliferator-activated receptor (PPAR)-α and its downstream target genes (CPT-1 and ACO) and PPAR-γ and its target genes (CD36 and LPL) mRNA expression in the kidney tissue. Furthermore, HKC enhanced the serum adiponectin levels while reducing inammation-induced cytokines, namely, tumor necrosis

factor-alfa (TNF-α), Interleukin (IL)-6, IL-1β, and IL-2in the kidney tissue of DN rats. Therefore, they suggested HKC as a potential anti-DN agent through activating PPARα/γ [3]. Similarly, HKC notably decreased total body weight and kidney weight, blood urea nitrogen (BUN), uric acid (UA), and urinary albumin levels in unilateral nephrectomy and streptozotocin injection in rats. It also improved renal brosis by inhibiting the cell number and extracellular matrix amount in the glomerulus. In addition, HKC markedly attenuated the oxidative stress parameters, including malondialdehyde (MDA) and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), while elevating the activity of anti-oxidant superoxide dismutase (SOD). Furthermore, it meaningfully downregulated phosphorylated p38MAPK, phosphorylated Akt (p-Akt), TNF-α, and TGF-β protein expressions in the kidney tissue of DN rats [4].

Tu and coworkers reported that HKC remarkably enhanced body weight and general status while decreasing kidney/body weight ratio, urinary protein, serum BUN, and creatinine (Cr) levels in unilateral nephrectomy and adriamycin- induced nephropathy in male Sprague-Dawley rats. It also improved renal brosis by reducing the cell numbers and rate of extracellular matrix in the glomerulus and reduced the number of ED1(+) and ED3(+) macrophages inltrating the glomeruli. In addition, HKC provided a signicant decrement in TNF-α, IL-2, TGF-β1, and phosphorylated p38MAPK protein expression in the kidney of adriamycin-induced nephropathy in rats [5]. Similarly, HKC

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strikingly attenuated body weight, serum albumin, SCr, and urinary albumin levels, and improved glomerular pathological changes in unilateral nephrectomy and adriamycininduced nephropathy in male Sprague-Dawley rats. Moreover, it notably downregulated the expression levels of p-Akt, p-p70S6K, p-mTOR, and TGF-β1in the rats’ renal tissue following adriamycin-induced nephropathy [6].

Cai etal. noticed that HKC rmly alleviated serum Cr, BUN, and urinary protein levels in chronic renal failure produced by adenine in male Sprague–Dawley rats. It also suppressed NOX1, NOX2, NOX4, α-SMA, and phosphorylated extracellular signal-regulated kinase (p-ERK) expression in kidney tissue [7]. Furthermore, Kim etal. showed that 70% ethanolic extract of ower and leaf of A. manihot markedly mitigated serum Cr, BUN, urinary albumin, glomerular and tubular damage in unilateral nephrectomy, excessive fat consumption, and streptozotocin induction in C57BL/6 mice. A. manihot extract also reduced the mRNA expression of TNFα, IL-6, and p-IκBα while elevating IL-10in kidney tissue [8]. Taken together, A. manihot and HKC may be effective candidates for improving CKD.

2.2 Clinical Studies

The renoprotective properties of A. manihot have been approved in several clinical studies. In this regard, Zhang etal. evaluated the impact of HKC (2.5g, 3 times/day) on 417 patients with biopsy-conrmed primary glomerular disease. They revealed that HKC strikingly decreased proteinuria after 24weeks of treatment. Surprisingly, the effect of HKC on proteinuria was more signicant than losartan potassium (50mg/day). In addition, no severe adverse effects were observed with HKC treatment [9]. Similarly, HKC showed promising results for treating IgA nephropathy (IgAN) patients. In this study, 1600 biopsy-proven cases of IgAN were randomized to receive either HKC (dosage of

2.5g, 3 times daily) or losartan potassium (dosage of 100mg daily) continuously over 48 weeks. Both groups notably diminished the 24-h proteinuria following 48weeks of treatment, and HKC produced similar results as losartan. In addition, the glomerular ltration rate (eGFR) did not differ signicantly in both HKC or losartan groups [10].

A meta-analysis conducted by Shi and colleagues involved 72 human clinical studies comprising 5895 patients with DN. They emphasized that the combined therapy of HKC and RAS blockers mitigated levels of urinary protein in 24h, rate of urinary albumin excretion, and serum Cr more effectively than RAS blockers alone. However, they did not nd any signicant changes in eGFR levels in both groups. In addition, no severe adverse effect was reported following HKC treatment, and HKC did not elevate the adverse effects rates.

It could be concluded that A. manihot may be a promising and safe treatment for ameliorating the severity of proteinuria as well as renal function in CKD patients.

3 Salvia miltiorrhiza andIts Major Active

Components: Tanshinone andSalvianolic Acid

The perennial owering plant Salvia miltiorrhiza (S. miltiorrhiza) is a member of Lamiaceae. Its roots are extensively

used in traditional Chinese medicine. Some major active ingredients of S. miltiorrhiza are salvianolic acid A and B, tanshinone I, IIA, and IIB [11].

3.1 Animal Studies

The ethyl acetate extract of roots of S. miltiorrhiza signicantly mitigated urine level, urinary albumin excretion, albumin/Cr ratio, serum Cr, BUN, and improved the pathological changes in streptozotocin-induced DN in male C57BL/6 mice. S. miltiorrhiza also elevated nuclear factor erythroid- 2- related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) mRNA expression while suppressing Keap-1 mRNA expression in the kidney of DN mice. They supported that S. miltiorrhiza ameliorates DN through the Nrf-2-mediated anti-oxidant system [12].

3.1.1 Salvianolic Acid A

Salvianolic acid A remarkably reduced kidney/body weight ratio, Scr, BUN, creatinine clearance rate, and MDA level while increasing body weight and SOD activity in 5/6 nephrectomized rats. It also downregulated TGF-β1 while upregulating bone morphogenetic protein 7 (BMP-7) and Smad6 protein expression levels in the kidney [13]. Furthermore, Zhang etal. found that salvianolic acid A dose- dependently alleviated TGF-β1, α-smooth muscle actin (α-SMA), TNF-α, IL-1β expression levels in 5/6 nephrectomized rats. It also suppressed nuclear factor-kappa B (NF- κB) and p38 mitogen- activated protein kinase (MAPK) signaling cascade in the kidneys of 5/6Nx rats [14]. Similarly, salvianolic acid A dosedependently stimulated the activity of SOD, catalase (CAT), and glutathione peroxidase (GPx) while diminishing MDA, reactive oxygen species (ROS), and NOX-4 levels in 5/6 nephrectomized rats. It also propagated p-Akt, p-GSK-3β, p-Nrf-2, and HO-1 levels in the renal tissue of 5/6Nx rats [15].

In minimal change disease (MCD) caused by adriamycin in rats, salvianolic acid A rmly attenuated Scr, BUN, and urinary levels of angiopoietin-like 4 (Angptl4). It also decreased Angptl4 while increasing PPARγ mRNA expression in MCD rats [16].

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3.1.2 Salvianolic Acid B

Salvianolic Acid B signicantly decreased urinary output, cystatin C, Scr, intercellular adhesion molecule-1, VCAM-1, IL-1β, Interleukin-6, and TNF-αmRNA expression in the kidney tissue of renal tubular damage induced by fatty acid in C57BL/6 mice. It also diminished endoplasmic reticulum stress markers and apoptosis by decreasing apoptotic Bax and c-caspase-3 while increasing anti-apoptotic BCL2expression [17]. In a model of renal injury caused by ischemia–reperfusion in Balb/c mice, salvianolic Acid B notably reduced Scr, BUN, MDA, IL-1β and TNF-α mRNA levels, and Keap-1 protein expression in kidney tissue. It also propagated Nrf-2 and HO-1 levels, and SOD and glutathione (GSH) activities in kidney tissue [18].

Hu and coworkers showed that salvianolic acid B markedly alleviated BUN, Scr, a-SMA, and protein expression of TGF-β and FGF-2, while increasing E-cadherin protein expression in the kidney tissue of unilateral ureteral obstruction- induced renal damage in C57BL/6 mice [19].

3.1.3 Tanshinone IIA

In streptozotocin-induced DN, Tanshinone IIA strikingly diminished urine albumin excretion rate, CRP, and MDA levels while enhancing SOD activity. It also provided a notable decrement in TGF-β1, P-selectin, and monocyte chemotactic protein-1 (MCP-1) mRNA expression levels in DN rats’ renal tissue [20]. Similarly, Tanshinone IIA remarkably attenuated mRNA expression of TGF-β1, thrombospondin-1 (TSP-1), glucose-regulated protein 78 (Grp78), and CHOP in kidneys of DN rats. In addition, Tanshinone IIA signicantly mitigated endoplasmic reticulum stress by decreasing the protein levels of p-PERK, p-elf2α, and activating transcription factor (ATF)-4in the renal tissue of streptozotocininduced DN in rats [21]. Liang etal. revealed that Tanshinone IIA ameliorated contrast-induced nephropathy through decreasing MDA and increasing Nrf-2 and HO-1 signaling pathways [22].

Taken together, S. miltiorrhiza and its main active ingredients may be promising candidates for modulating CKD through anti-oxidative and anti-brotic effects.

3.2 Clinical Studies

Zhou and coworkers conducted a meta-analysis on 21 clinical studies involving 1857 patients with CKD.They realized that S. miltiorrhiza signicantly attenuated BUN, Scr, 24-h urine protein levels, microalbuminuria, β2-macroglobulin, and cystatin C (CysC) while improving GFR levels in CKD patients. Neither the safety nor the adverse effects were meaningfully different between the extract and control groups [23].

Similarly, Xu etal. analyzed 16 clinical studies involving 1696 cases of hypertensive nephropathy. They supported that sodium tanshinone IIA sulfonate combined with angiotensin II receptor blockers (ARBs) remarkably mitigated 24h urinary protein, Scr, cystatin-C, urinary immunoglobulin G, urine transferrin level, systolic (SBP) and diastolic blood (DBP) pressures while propagating GFR compared to monotherapy with ARB in patients with hypertensive nephropathy [24].

It could be summarized that supplementation therapy with S. miltiorrhiza and its constituents may be effective and safe in treating CKD patients.

4 Berberine

Berberine is an alkaloid widely found in the barks, roots, rhizomes, and stems of species Berberis (B. vulgaris, B. aris-

tata, B. aquifolium) and Coptis (Coptis japonica, Coptis chinensis). Berberine possesses plenty of promising

pharmacological effects, including anti-inammatory, antioxidant, anti-diabetic, anti-hypertensive, hypolipidemic, cardioprotective, and renoprotective effects [25, 26].

4.1 Animal Studies

Berberine notably decreased MDA level while enhancing SOD and CAT activities in the kidney tissue of unilateral ureteral obstruction (UUO)-induced kidney injury in Sprague-Dawley rats. It also signicantly diminished TGFβ1, α-SMA, and phosphorylated Smad3 (pSmad3) expression in the kidney tissue of UUO rats [27]. Qin et al. suggested that berberine ameliorates diabetic kidney disease by decreasing the expression as well as dynamin-related protein 1 (Drp1) translocation from the cytoplasm to the mitochondria [28].

In the streptozocin-induced DN model, berberine markedly reduced kidney/body weight, BUN, Scr, 24-h urinary protein levels, and protein expression of extracellular matrix protein deposition-related markers. It also promoted the AMP-activated protein kinase (AMPK) phosphorylation and autophagy-related markers in DN rats [29]. Similarly, berberine meaningfully alleviated Scr, BUN, as well as TGF-β, vimentin, and α-SMA expression in DN rats [30]. Furthermore, Zhu and coworkers noticed that berberine strikingly mitigated kidney/body weight ratio, 24-h urinary protein, Scr, BUN, IL-1β, IL-6, and MCP-1 levels in the kidney tissue of streptozocin-induced DN rats. Berberine also suppressed the TLR-4 and NF-κB cascade through decreasing TLR-4 protein level, p-IκBα/IκBα, and p-p65/p65in DN rats [31]. In addition, berberine provided a signicant decrement in matrix metallopeptidase (MMP)-9, tissue inhibitor

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Fig. 2 The anti-CKD and reno-protective mechanisms of berberine. Malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), Interleukin (IL), transforming growth factor-β1 (TGF-β1), matrix metallopeptidase (MMP), AMP-activated protein

matrix metalloproteinase (TIMP)-1 and -2, TGF-β1, bronectin, and type IV collagen while increasing MMP2 expression levels in streptozocin-induced DN in the rat [32].

In spontaneously hypertensive rats, berberine remarkably attenuated hypertension, Ang II, aldosterone, kidney-injury molecule (KIM-1), IL-6, IL-17, IL-23, and osteopontin [33]. Tian and coworkers showed that berberine rmly alleviated mean arterial pressure, NOX2 and 4, Erk1/2, and iNOS while stimulating copper/zinc superoxide dismutase levels in hypertensive rats [34].

Taken together, berberine may effectively protect against CKD through several mechanisms, including anti-oxidative, anti-inammatory, and anti-brotic impacts (Fig.2).

4.2 Clinical Studies

Dai and coworkers evaluated the impact of berberine (0.1g, 3 times daily) on 69 hypertensive patients with type 2 diabetes mellitus. They revealed that berberine notably decreased Scr, urine albumin-to-creatine ratio, renal damage markers including osteopontin and KIM-1, as well as inammatory markers, including VCAM-1 and CRP.Berberine also inhibited oxidative stress through reducing MDA while stimulat-

kinase (AMPK), tissue inhibitor matrix metalloproteinase (TIMP), nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), toll-like receptor 4

ing superoxide dismutase, GSH-Px, and total anti-oxidant capacity (TAC) activities in hypertensive and type 2 diabetes mellitus patients [35]. Similarly, Li and coworkers determined the effects of berberine (0.4g, 3 times daily) on 114 patients with type 2 diabetes mellitus. Berberine signicantly diminished hs-CRP, BUN, urine albumin/Cr ratio, and cystatin C while improving eGFR level than the control group. Besides that, no important adverse effects were observed following treatment with berberine [36].

5 Zingiber ocinale andIts Constituents:

6-Gingerols and6-Shogaols

Zingiber ofcinale (Z. ofcinale), popularly known as ginger, is a perennial herb belonging to Zingiberaceae [37]. Its roots are widely used as a spice and also in traditional medicine worldwide. It has been emphasized that Z. ofcinale has anti-oxidant, anti-inammatory, anti-microbial, anti-emetic, anti-diabetic, cardioprotective, and renoprotective effects. The phenolic constituents of Z. ofcinale are mainly responsible for their several effects, including 6-gingerols and 6-shogaols [38, 39].

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5.1 Animal Studies

In the model of streptozocin-induced DN, Z. ofcinale extract signicantly decreased Scr, BUN, and MDA while enhancing GSH level, and activities of SOD and CAT in renal tissue. In addition, Z. ofcinale markedly diminished inammatory cytokines, namely, TNF-α, IL-6, and IL-1β, and apoptosis (cytochrome c, caspase-3) in the kidney tissue of streptozocin-induced DN in rats [40].

Furthermore, Z. ofcinale extract notably reduced MDA and TNF-α levels while increasing activities of TAC, SOD, catalase, Gpx, and expression of Nrf-2in the kidney tissue of ethanol-induced kidney injury in ats [41].

In the model of mercuric chloride-induced kidney injury, Z. ofcinale extract meaningfully elevated GSH level, SOD, catalase, GPx, glutathione reductase, and glutathione- S- transferase (GST) activities while decreased MDA levels in kidney tissue [42]. Similarly, Z. ofcinale extract rmly stimulated GSH levels, GPx, GST, and CAT in the kidney tissue of lead-induced renal toxicity in rats [43].

5.1.1 6-Shogaol

In the renal ischemia–reperfusion (I/R) model, 6-shogaol notably diminished Scr, BUN, kidney neutrophil gelatinaseassociated lipocalin (NGAL), IL-6, MCP-1, macrophage inammatory protein-2 (MIP-2), and keratinocyte chemoattractant expression. It also stimulated HO-1 expression in I/R-induced kidney injury in mice [44]. In addition, 6-shogaol also protects against streptozocin-induced DN through propagating Nrf-2mRNA expression in C57BL/6 male mice [45].

Gwon etal. revealed that 6-shogaol remarkably mitigated Scr, BUN, MDA levels, and KIM-1, NGAL, NOX4, TNF-α, IL-6, and MCP-1 mRNA expression in acute kidney injury following cisplatin in mice. It also elevated GSH levels, SOD, and catalase activities in kidney tissue [46].

5.1.2 6-Gingerol

In streptozocin-induced DN, 6-gingerol strikingly reduced Scr, BUN, MDA, CRP, IL-6, IL-1β, and TNF-α levels. Moreover, it elevated the GSH level, and activities of SOD and catalase in the renal tissue of DN rats [47]. 6-Gingerol also alleviated Scr, BUN, and MDA levels while improving GSH levels and pathological changes in the kidney tissue of gentamicin-induced renal injury [48].

Salihu and coworkers supported that 6-gingerol markedly reduced MDA and hydrogen peroxide levels while increasing anti-oxidant activities in carbendazim-induced renal damage in rats [49].

In the mercuric chloride-induced kidney injury model, 6-gingerol rmly propagated GSH level, SOD and CAT, GR, GPx, and GST activities while reducing MDA level in kidney tissue [42].

5.2 Clinical Studies

Imani etal. investigated the effects of Z. ofcinale (1000mg/ day) on 36 patients on peritoneal dialysis. They showed that Z. ofcinale notably mitigated fasting glucose levels in serum, which is an important risk factor for DN, hyperinsulinemia, and cardiovascular disorders [50].

6 Punica granatum andIts Major

Constituent Ellagic Acid

Punica granatum (P. granatum), which is popularly famous as pomegranate, is a small deciduous tree and a member of Punicaceae. It is mostly cultivated in the Mediterranean countries, including India, Iran, Turkey, and China. Several pharmacological effects have been attributed to P. granatum fruit, including anti-oxidant, anti-inammatory, antidiabetic, hepatoprotective, cardioprotective, and renoprotective properties [51, 52]. In addition, ellagic acid (EA) is one of the major and well-studied active polyphenolic compounds found in pomegranate fruits [53, 54].

6.1 Animal Studies

In the model of streptozotocin-induced DN, the P. granatum leaves extract containing a high amount of avonoids (PGFF) meaningfully decreased Scr, BUN, urinary total protein, urine volume, and MDA level in rats. PGFF also improved histopathological changes and anti-oxidant markers in the kidneys of DN rats [55]. Similarly, the methanolic extract of P. granatum leaves (MPGL) remarkably diminished Scr, BUN, and MDA levels while promoting GSH level, CAT, and SOD activities in the kidney tissue of streptozotocininduced DN in rats [56]. MPGL also reduced oxidative stress and TNF-α level in the rat’s kidney tissue of gentamicininduced nephropathy [57].

P. granatum peel ethanol extract (PPEE) notably mitigated oxidative stress markers, C-reactive protein, and caspase- 3 while elevating Bcl-2 renal expression in vancomycin-induced kidney injury in the rat [58]. In addition, P. granatum juice markedly attenuated levels of nitric oxide (NO) and MDA while enhancing anti-oxidant status in the kidney tissue of carbon tetrachloride-induced nephrotoxicity in rats [59].

6.1.1 Ellagic Acid (EA)

In the model of streptozotocin-induced DN, EA rmly alleviated Scr, BUN, MDA, and TNF-α levels while increasing SOD activity in kidney tissue. EA also suppressed the HMGB1-TLR-4-NF-кB pathway by downregulating TLR-4, Interleukin-1 receptor-associated kinase 4 (IRAK4), TNF

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Fig. 3 The anti-CKD and reno-protective mechanisms of Punica gra- natum and its main active constituent, EA.Interleukin (IL), Interleukin-1

receptor-associated kinase 4 (IRAK4), tumor necrosis factor-α (TNF- α), TNF receptor associated factor 6 (TRAF6), transforming growth

factor-β1 (TGF-β1), nicotinamide adenine dinucleotide phosphate oxi-

receptor-associated factor 6 (TRAF6), inhibitor of NF-κB kinase (IKK-β), NF-κBp65, and HMGB1 protein expression in the kidney tissue of DN mice [60]. EA also ameliorated sodium arsenite-induced renal injury in rats by anti-oxidative effects [61].

In chronic renal failure induced by 5/6 nephrectomy, EA signicantly decreased urine volume, urine protein, BUN, Scr, MDA, TNF-α, IL-6, and ICAM-1 level while increasing GSH level and superoxide dismutase activity in renal tissue. In addition, EA markedly diminished miR-182, TGF-β1, bronectin, and Bax while stimulating FOXO3a and Bcl-2 expression levels in rats [62]. Similarly, in the renal ischemic–reperfusion injury model, EA notably alleviated TNFα, IL-1β, IL-6, and MCP-1, MDA, LDH, iNOS, COX-2 levels, Bax and caspase-3 expression while promoted GSH level, SOD activity, and Bcl-2 expression in kidney tissue. Furthermore, EA inhibited the p-JAK1, p-JAK2, p-STAT1, and NOX4 expression levels [63].

In the carbon tetrachloride-induced kidney damage model, EA meaningfully attenuated MDA level, and COX-2, TNF-α, NF-κB, and vascular endothelial growth factor family (VEGF) expression. It also propagated GSH level, CAT activity, and Nrf-2 expression in kidney tissue [64]. Moreover, EA suppressed MDA, TNF-α, IL-6 levels, NF-κB, and Bax expression while increasing anti-oxidant markers following amikacin-induced nephrotoxicity in rats [65].

dase (NOX), Toll-like receptor 4 (TLR-4), inhibitor of nuclear factor kappa-B kinase (IKK-β), nuclear factor-kappaB (NF-κB), nuclear factor erythroid-2-related factor 2 (Nrf-2), High mobility group box 1 (HMGB1), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT)

Collectively, P. granatum and its main active constituent, EA, may ameliorate CKD through several mechanisms, including anti-oxidative, anti-inammatory, anti-apoptotic, and anti-brotic effects (Fig.3).

7 Vitis vinifera

Vitis vinifera (V. vinifera), commonly known as grape, is a owering plant belonging to Vitaceae. Nowadays, V. vinifera is cultivated in almost every country around the world. The grape juice and seeds have high levels of polyphenols and anti-oxidants and show multiple pharmacological properties, containing immunomodulatory, anti-oxidant, antiinammatory, anti-atherosclerotic, anti-diabetic, anti-aging, cardioprotective, and renoprotective properties [66].

7.1 Animal Studies

Grape seed proanthocyanidin extracts (GSPE) signicantly ameliorated endoplasmic reticulum stress-induced apoptosis through diminishing GRP78, p-ERK, and caspase-12 expression in streptozotocin-induced DN in rats [67]. Similarly, GSPE markedly reduced levels of Scr, BUN, and MDA while increasing anti-oxidant activities in DN rats. GSPE

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307

also meaningfully propagated Nrf-2, HO-1, GST, and NQO1 renal mRNA expression [68]. Following the carboplatin and thalidomide-induced nephrotoxicity, GSPE rmly alleviated p53 expression, TNF-a, IL-6, MDA, and NO levels, while elevating GSH, GST, TAC levels, SOD, and catalase, activities in renal tissue [69].

In doxorubicin-induced DN, aqueous extracts of V. vinif- era fruits remarkably attenuated Scr, BUN, and hs-CRP while stimulating the mRNA expression of Nrf-2in kidney tissue [70]. In addition, V. vinifera seed extract notably decreased the Scr, MDA, and IL-6 levels while enhancing SOD activity in amiodarone-induced nephrotoxicity in rats [71].

7.2 Clinical Studies

Imani et al. determined the impacts of grape seed extract (GSE, 2100mg/day) by evaluating 33 patients with chronic kidney disease. They revealed that GSE meaningfully attenuated urinary protein, MDA, protein carbonylation, H2O2, and CRP levels while propagating GFR, CAT, GPx levels, and SOD activity [72].

Taken together, V. vinifera may ameliorate renal failure and chronic kidney disease through anti-oxidant and antiinammatory activities.

8 Curcuma longa andIts Major

Component: Curcumin

In sodium arsenate-induced kidney injury in mice, curcumin markedly diminished IL-1β, IL-6, TNF-α, Interferongamma (IFN-γ), TGF-β1, and NF-κB mRNA levels and suppressed MAPK signaling through decreasing P-JNK, P-ERK1/2, and P-p38 phosphorylation in kidney tissue. Additionally, curcumin activated the Nrf-2 signaling cascade by enhancing Nrf-2, NQO1, as well as HO-1 protein expression [77]. Cao etal. also suggested that curcumin meaningfully alleviated levels of MDA and NO, IL-1β, IL-6, and TNF-α while elevating SOD, CAT, and GSH-Px activities in gentamicin-induced nephrotoxicity in rats. In addition, curcumin inhibited apoptosis by decreasing caspase-3 and Bax while enhancing Bcl-2 expression [78].

Curcumin remarkably mitigated NLRP3 inammasome activation by decreasing IL-1β, NLRP3, ASC, and caspase1 mRNA and protein expression in hyperuricemia and kidney inammation following potassium oxonate consumption in mice [79]. Furthermore, in passive Heymann nephritis model in rats, curcumin rmly attenuated Scr, BUN, and MDA levels while increasing GSH levels, and SOD, and catalase in kidney tissue. Besides that, curcumin suppressed Bax, Caspase-3, p62, PI3K, p-AKT, and p-mTOR while stimulating Bcl-2, Nrf-2, beclin1, and HO-1proteins expression in kidney tissue [80].

In cisplatin-induced kidney damage in rats, curcumin provided a signicant decrement in Scr, BUN, MDA levels, ERK1/2 phosphorylation, NF-κB expression, Bax/Bcl-2 ratio, and TNF-α, IL-6, KIM-1, and NGAL mRNA levels. In contrast, curcumin increased GSH levels and IL-10 mRNA expression in renal tissue [81].

Curcuma longa (C. longa), commonly known as turmeric, is a perennial rhizomatous herb member of Zingiberaceae. It is chiey cultivated in Asia, India, Iran, and China. Curcumin is the major and well-studied polyphenol isolated from the rhizome of C. longa. Curcumin has many promising pharmacological properties, including anti-oxidant, antiinammatory, immunomodulatory, anti-microbial, anti-cancer, neuroprotective, hepatoprotective, and renoprotective properties [73, 74].

8.2 Clinical Studies

Alvarenga and coworkers evaluated the effects of C. longa containing 95% curcumin (2.5g, 3 times/week) on 31 hemodialysis patients. They noticed that curcumin remarkably diminished the mRNA expression of NF-kB and hs-CRP levels [82]. Similarly, curcumin (1g/day for 12weeks) markedly propagated CAT and GPx activities in hemodialysis patients. Besides that, hs-CRP and MDA levels, and GR activity did not signicantly change [83].

8.1 Animal Studies

cumin (320mg/day) on non-diabetic or diabetic proteinuric

In a model of kidney injury induced by doxorubicin, powdered dried rhizomes of C. longa signicantly decreased MCP-1 and TGF-β1 levels, pathological changes, and desmin, vimentin, and ED-1+ cells immunostaining in the rat kidney tissue [75]. Similarly, curcumin notably reduced urinary protein, MDA levels, protein expression of NF-κB p65, and Keap-1, while stimulating the protein expression of HO-1, NQO-1, Nrf-2, IκBα, and SOD activity in the doxorubicin- induced nephrotic syndrome [76].

CKD.They revealed that curcumin rmly alleviated MDA levels in non-diabetic patients while elevating anti-oxidant markers in diabetic proteinuric CKD patients. They reported no meaningful differences in the urinary protein, eGFR, and Nrf-2 activation [84]. Furthermore, curcumin (500mg/tablet twice for 6 months) strikingly attenuated MDA, MCP-1, IL-4, and IFN-γ levels in CKD patients [85].

involving 290 diabetic kidney disease (DKD) patients

Osorio and coworkers determined the impacts of cur-

Additionally, a meta-analysis of 5 human clinical studies

308

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V. BaradaranRahimi and V. R. Askari

Fig. 4 The anti-CKD and reno-protective mechanisms of Curcuma longa and its major active constituent, curcumin. Nuclear factor-κB

(NF-κB), nuclear factor erythroid-2-related factor 2 (Nrf-2), inhibitor of nuclear factor kappa-B (Iκβα), heme oxygenase-1 (HO-1), mammalian target of rapamycin (mTOR), NAD(P)H quinone dehydrogenase 1 (NQO1), phosphorylation-extracellular signal-regulated kinase

emphasized that curcumin notably diminished Scr, total cholesterol, SBP, and fasting blood glucose. In contrast, curcumin showed no signicant changes in BUN, urinary protein, triglyceride, and diastolic blood pressure levels [86]. Emami etal. also analyzed 10 clinical studies involving 523 CKD patients. In comparison with the control group, they found no notable changes in IL-6, TNF-α, and hs-CRP levels following curcumin consumption [87]. In contrast, a metaanalysis consisting of nine clinical studies supported that curcumin markedly mitigated total cholesterol and TNF-α in CKD patients [88].

Collectively, C. longa and its main active constituent, curcumin, may ameliorate CKD through several mechanisms, including anti-oxidative, anti-inammatory effects and PI3K/AKT/mTOR, Nrf-2/HO-1, and NF-κB signaling pathways (Fig.4).

9 Nigella sativa

Nigella sativa (N. sativa), commonly known as black cumin, is an annual herbaceous owering plant belonging to Ranunculaceae [89]. Its small and black seeds have been used in many traditional foods and as folk medicine.

(p-ERK), kelch-like ECH-associated protein 1 (Keap-1), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), Interleukin (IL), transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor-α (TNF-α), NLR family pyrin domain containing 3 (NLRP3), kidney-injury-molecule (KIM-1), Interferongamma (IFN-γ), neutrophil gelatinase-associated lipocalin (NGAL)

Thymoquinone is the major active ingredient of seeds of N. sativa. Several pieces of evidence support that N. sativa has anti-tussive, anti-oxidant, anti-cancer, anti-inammatory, anti-anxiety, analgesic, hepatoprotective, and nephroprotective properties [90, 91].

9.1 Animal Studies

In the UUO model in rats, 70% hydro-ethanolic extract of N. sativa signicantly suppressed the levels of angiotensin II,

MCP-1, MDA, and TNF-α in kidney tissue. It also increased GSH levels, and activities of SOD and catalase [92]. In addi- tion, N. sativa oil notably diminished total oxidant status and lipid hydroperoxide levels while enhancing total anti-oxidant status, paraoxonase, and ceruloplasmin activities in radiationinduced kidney damage in rats [93].

In cisplatin-induced kidney damage, N. sativa oil and thymoquinone remarkably attenuated Scr, BUN, and MDA levels while stimulating the anti-oxidant status in rat kidney tissue [94]. Similarly, 70% hydro-ethanolic extract of N. sativa signicantly improved histopathological changes and GSH levels in kidney tissue [95].

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9.2 Clinical Studies

Alam and coworkers demonstrated the impact of N. sativa oil (2.5mL, taken orally, once daily) on 150 patients with Stages 3 and 4 of CKD.They showed that N. sativa oil markedly diminished the blood urea, Scr, and 24-h urinary protein while notably increasing the 24-h total urine volume and GFR level [96]. Meanwhile, a meta-analysis of 19 clinical studies involving 1295 participants emphasized that N. sativa notably mitigated ALP and BUN levels [97].

10 Rosmarinus ocinalis andIts Major

Constituent: Rosmarinic Acid

The herb Rosmarinus ofcinalis, common name rosemary, is an aromatic evergreen perennial shrub of Lamiaceae. Its dark green elongated and aromatic leaves are used to season food, as well as in folk medicine for centuries. The main active constituents of R. ofcinalis are carnosic acid, carnosol, and rosmarinic acid. Previous studies revealed that R. ofcinalis and its active components possessed anti-nociceptive, antioxidant, anti-inammatory, neuroprotective, anti-depressant, and nephroprotective properties [98, 99].

10.1 Animal Studies

In carbon tetrachloride-induced nephropathy in mice, R. ofcinalis signicantly reduced Scr, BUN, LDH, and MDA

while increasing anti-oxidant markers activities in kidney tissue [100]. Similar to this, rosemary essential oil notably diminished urea, Scr, and MDA levels while improving histopathological changes, total anti-oxidant concentration, CAT, and GPx activities in diethylnitrosamine-induced renal injury in rats [101]. R. ofcinalis essential oil also decreased urea, creatinine, uric acid, MDA, and H2O2 levels while improving histological changes and anti-oxidant activities in potassium dichromate-induced kidney damage in rats [102].

10.1.1 Rosmarinic Acid

Rosmarinic acid markedly attenuated MDA, NO levels, and mRNA expression of IL-1β, IL-6, and TNF-α while elevating SOD, catalase, and TAC activities in kidney injury following cisplatin administration in mice. Rosmarinic acid also stimulated the Nrf-2 signaling cascade through stimulating Nrf-2 and HO-1 while inhibiting Keap-1 mRNA expression in kidney tissue [103]. In chlorpyrifos-induced kidney injury in rats, rosmarinic acid rmly mitigated serum urea, Scr, KIM-1, ROS, MDA, NO, IL-1β, TNF-α, and NF-κB p65 levels while promoting GSH, SOD, and CAT activities in kidney tissue. Additionally, rosmarinic acid strikingly suppressed Bax, caspase-3, and Keap-1 while stimulating the

expression of Bcl-2, Nrf-2, HO-1, and Sirtuin 1 (SIRT1) in kidney tissue [104].

Rosmarinic acid also prevented MDA levels and histopathological changes while propagating GSH levels and Nrf-2 mRNA levels in chromium-induced renal injury in rats [105]. In cadmium-induced nephrotoxicity, rosmarinic acid considerably reduced CRP, IL-1β, IL-6, TNF-α, ROS, NO, H2O2, and MDA levels while stimulating GSH, GPx, and GR levels, as well as SOD and CAT activities. Furthermore, rosmarinic acid hampered caspase-3, 8, and 9, NF-κB, protein kinase C (PKC), tumor necrosis factor receptor, TGF-β1, SMAD3, and α-SMA expression in kidney tissue [106].

Acknowledgments This study was supported by the research council of Mashhad University of Medical Sciences.

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7. Cai HD, Su SL, Qian DW, Guo S, Tao WW, Cong XD, etal. Renal protective effect and action mechanism of Huangkui capsule and its main ve avonoids. J Ethnopharmacol. 2017;206:152–9.

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