Yiqi‑Yangyin‑Huoxue Formula Activates The VDR/DDIT4/mTOR Axis To Restore Autophagy And Protect Kidneys in Diabetic Nephropathy Rats—Actionable Insights For “herb For Kidney Disease Treatment?”
Dec 24, 2025
Section 2 Results (English translation, optimized for developers evaluating herb for kidney disease treatment?)
2.1 Effects of Yiqi‑Yangyin‑Huoxue Formula on 24 h Urinary Total Protein (24 h‑UTP) and Serum Biochemistry in DN Rats
Compared with the normal control group, the model control group showed significantly increased 24 h‑UTP and serum GLU, CHO, TG, ALT, BUN, and Crea, and decreased ALB (P<0.05), indicating renal injury in the model controls. Versus the model controls, valsartan and both doses of Yiqi‑Yangyin‑Huoxue formula significantly decreased 24 h‑UTP and serum GLU, CHO, TG, ALT, BUN, and Crea, while increasing ALB (all P<0.05). See Tables 2–3.
Developer note: 24 h‑UTP, Crea, and BUN are translationally relevant efficacy readouts for kidney protection. These endpoints align with regulatory expectations for adjunctive herbal interventions..
Table 2. Effects of Yiqi Yangyin Huoxue Formula on 24h-UTP, Fasting Blood Glucose and Blood Lipids in Diabetic Nephropathy Rats (x̄±s)
| Group | n | Dose (g/kg) | 24h-UTP (mg/24h) | GLU (mmol/L) | CHO (mmol/L) | TG (mmol/L) |
|---|---|---|---|---|---|---|
| Normal Control | 6 | 0 | 11.24 ± 3.69 | 6.84 ± 1.3 | 1.76 ± 0.34 | 0.92 ± 0.22 |
| Model Control | 8 | 0 | 42.99 ± 6.55* | 34.53 ± 2.74* | 5.28 ± 0.37* | 2.20 ± 0.16* |
| Irbesartan Group | 8 | 0.00833 | 20.12 ± 4.98* | 19.94 ± 2.01* | 2.14 ± 0.23* | 1.18 ± 0.22* |
| YYH Formula Low Dose | 8 | 11 | 21.19 ± 3.90* | 20.94 ± 2.49* | 2.28 ± 0.27* | 1.21 ± 0.19* |
| YYH Formula High Dose | 8 | 22 | 19.36 ± 3.21* | 19.80 ± 2.12* | 2.15 ± 0.33* | 1.20 ± 0.14 |
Table 3. Effects of Yiqi Yangyin Huoxue Formula on Renal Function in Diabetic Nephropathy Rats (x̄±s)
| Group | n | Dose (g/kg) | ALB (g/L) | ALT (U/L) | BUN (mmol/L) | Scr (μmol/L) |
|---|---|---|---|---|---|---|
| Normal Control | 6 | 0 | 28.3 ± 0.38 | 30.18 ± 1.42 | 6.24 ± 0.23 | 53.35 ± 2.42 |
| Model Control | 8 | 0 | 18.5 ± 0.42* | 58.04 ± 2.13* | 14.15 ± 0.65* | 102.15 ± 3.34* |
| Irbesartan Group | 8 | 0.00833 | 22.4 ± 0.51* | 41.30 ± 2.05* | 8.94 ± 0.41* | 77.12 ± 2.84* |
| YYH Formula Low Dose | 8 | 11 | 22.8 ± 0.49* | 42.19 ± 1.65* | 9.01 ± 0.54* | 79.09 ± 3.01* |
| YYH Formula High Dose | 8 | 22 | 23.2 ± 0.46* | 41.08 ± 1.72* | 8.82 ± 0.37* | 78.83 ± 2.28* |
*P < 0.05 versus Model Control
TCM HERB CISTANCHE FOR KIDNEY DISEASE TREATMENT
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Email:wallence.suen@wecistanche.com
2.2 Effects on Renal Histopathology
Normal controls displayed uniform distribution of intraglomerular cells and matrix, no obvious interstitial hyperplasia, largely plump renal tubules, and essentially normal renal structure. Model controls showed capillary congestion/dilation in glomeruli, tubular epithelial edema, cellular swelling, cytoplasmic rarefaction and vacuolization, mesangial proliferation (moderate), mild interstitial connective tissue hyperplasia, and diffuse inflammatory infiltration. Versus model controls, the valsartan and Yiqi‑Yangyin‑Huoxue groups showed only mild tubular epithelial edema, uniform glomerular cell/matrix distribution, no obvious interstitial hyperplasia, occasional inflammatory cells, and markedly improved pathology. Pathology scores: model control = 16 (severe injury); all treatment groups had significantly reduced scores. See Table 4 and Figure 1.
Developer note: Histological improvement corroborates functional markers and supports disease‑modifying potential rather than purely symptomatic effects.
Table 4. Effects of Yiqi Yangyin Huoxue Formula on Renal Histopathological Grading and Injury Score in Diabetic Nephropathy Rats
| Group | n | Dose (g/kg) | Histopathological Injury Score (0–3) per Index | Total Score |
|---|---|---|---|---|
| Normal Control | 6 | 0 | 0, 0, 0, 0, 0 | 0 |
| Model Control | 8 | 0 | 1, 2, 3, 3, 3 | 16 |
| Irbesartan Group | 8 | 0.00833 | 1, 1, 2, 2, 2 | 10 |
| YYH Formula Low Dose | 8 | 11 | 1, 1, 2, 2, 2 | 8 |
| YYH Formula High Dose | 8 | 22 | 1, 1, 2, 2, 2 | 7 |
Injury grading: Normal = 0; Mild = 1; Moderate = 2; Severe = 3
Each score corresponds to a different renal pathological feature (glomerular, tubular, interstitial, fibrosis, and inflammatory infiltration)
2.3 Effects on Renal Vdr, Ddit4, Mtor, Beclin1, and Ulk1 mRNA
Versus normal controls, model controls had significantly downregulated Vdr, Ddit4, Beclin1, and Ulk1 mRNA and upregulated Mtor mRNA (P<0.05), indicating mTOR pathway activation and autophagy suppression. Compared with model controls, valsartan and both doses of Yiqi‑Yangyin‑Huoxue significantly upregulated Vdr, Ddit4, Beclin1, and Ulk1 mRNA and downregulated Mtor mRNA (P<0.05). See Table 5.
Developer note: The pattern (↑Vdr/DDIT4/Beclin1/Ulk1; ↓Mtor) is consistent with an autophagy‑restorative mechanism via VDR→DDIT4→mTOR.
Table 5. Effects of Yiqi Yangyin Huoxue Formula on mRNA Expression of Vdr, Ddit4, Mtor, Beclin1, Ulk1 in Renal Tissue (x̄±s, n=3)
| Group | Dose (g/kg) | Vdr/2^-ΔΔCt | Ddit4/2^-ΔΔCt | Mtor/2^-ΔΔCt | Beclin1/2^-ΔΔCt | Ulk1/2^-ΔΔCt |
|---|---|---|---|---|---|---|
| Normal Control | 0 | 1.00 ± 0.00* | 1.00 ± 0.00* | 1.00 ± 0.00* | 1.00 ± 0.00* | 1.00 ± 0.00* |
| Model Control | 0 | 0.29 ± 0.02* | 0.12 ± 0.02 | 3.41 ± 0.55 | 0.23 ± 0.02 | 0.09 ± 0.01 |
| Irbesartan Group | 0.00833 | 0.63 ± 0.01* | 0.55 ± 0.01* | 1.65 ± 0.02* | 0.49 ± 0.02* | 0.39 ± 0.01* |
| YYH Formula Low Dose | 11 | 0.64 ± 0.02* | 0.56 ± 0.02* | 1.66 ± 0.05* | 0.46 ± 0.04* | 0.40 ± 0.02* |
| YYH Formula High Dose | 22 | 0.63 ± 0.02* | 0.57 ± 0.02* | 1.73 ± 0.13* | 0.49 ± 0.03* | 0.41 ± 0.01* |
*P < 0.05 vs Model Control
2.4 Effects on Renal VDR, DDIT4, mTOR, p‑mTOR, Beclin‑1, and ULK1 Proteins
Versus normal controls, the model controls showed significantly reduced VDR, DDIT4, Beclin‑1, and ULK1 proteins, increased mTOR and p‑mTOR, and a decreased p‑mTOR/mTOR ratio (P<0.05). Versus model controls, valsartan and both Yiqi‑Yangyin‑Huoxue doses significantly upregulated VDR, DDIT4, Beclin‑1, and ULK1 proteins (P<0.05), downregulated mTOR and p‑mTOR, and increased the p‑mTOR/mTOR ratio (P<0.05). See Table 6 and Figure 2.
Developer note: Protein‑level confirmation strengthens the mechanistic claim and provides candidate pharmacodynamic biomarkers for translation.
Table 6. Effects of Yiqi Yangyin Huoxue Formula on Protein Expression of VDR, DDIT4, mTOR, p-mTOR, Beclin1, ULK1 in Renal Tissue (x̄±s, n=3)
| Group | Dose (g/kg) | VDR/β-actin | DDIT4/β-actin | mTOR/β-actin | p-mTOR/β-actin | mTOR/p-mTOR | Beclin1/β-actin | ULK1/β-actin |
|---|---|---|---|---|---|---|---|---|
| Normal Control | 0 | 0.68 ± 0.02* | 0.63 ± 0.02* | 0.18 ± 0.01* | 0.29 ± 0.01* | 1.64 ± 0.06* | 0.64 ± 0.04* | 0.64 ± 0.01* |
| Model Control | 0 | 0.27 ± 0.02 | 0.31 ± 0.01 | 0.89 ± 0.01 | 0.89 ± 0.01 | 1.01 ± 0.02 | 0.31 ± 0.02 | 0.25 ± 0.02 |
| Irbesartan Group | 0.00833 | 0.41 ± 0.02* | 0.45 ± 0.01* | 0.51 ± 0.01* | 0.59 ± 0.01* | 1.16 ± 0.04* | 0.41 ± 0.02* | 0.39 ± 0.01* |
| YYH Formula Low Dose | 11 | 0.42 ± 0.01* | 0.47 ± 0.01* | 0.52 ± 0.01* | 0.60 ± 0.01* | 1.16 ± 0.02* | 0.42 ± 0.01* | 0.40 ± 0.02* |
| YYH Formula High Dose | 22 | 0.43 ± 0.02* | 0.47 ± 0.01* | 0.55 ± 0.02* | 0.60 ± 0.01* | 1.08 ± 0.01* | 0.41 ± 0.02* | 0.40 ± 0.01* |
*P < 0.05 vs Model Control
3 Discussion (English translation, developer‑optimized)
Diabetic nephropathy (DN) is characterized by microvascular injury and progresses from diffuse thickening of the glomerular capillary basement membrane to mesangial cell/matrix proliferation and finally nodular sclerosis. DN pathogenesis involves disordered glucose/lipid metabolism, inflammatory activation, oxidative stress, and dysregulated autophagy/apoptosis [20]. Autophagy abnormalities are pivotal in DN [21]: basal autophagy supports organelle turnover and restrains fibrosis. Hyperglycemia suppresses autophagy (e.g., ↓Beclin‑1), leading to accumulation of damaged organelles and cytotoxic byproducts, cellular injury, and DN progression. Activating autophagy protects renal tubular epithelial cells from high‑glucose injury and restores function [22], making autophagy activation a key therapeutic strategy.
Activation of the VDR/DDIT4/mTOR axis modulates autophagy and mitigates DN pathology [10]. VDR promotes autophagy initiation via Beclin‑1, mTOR regulation, intracellular Ca2+, and lysosome maturation [23–24]. DDIT4 (REDD1) regulates cell survival/proliferation; overexpression inhibits high‑glucose–induced mesangial proliferation, implicating DDIT4 in DN [11]. mTOR (particularly mTORC1) is the primary negative regulator of autophagy in DN, integrating nutrient/stress signals at the lysosomal surface [25]. VDR can increase DDIT4, thereby suppressing mTORC1 and inducing autophagy to slow DN progression [26]. ULK1 complex activation initiates autophagy [27]; Beclin‑1 is essential for autophagosome formation and reflects autophagy initiation strength [28].
Our data: DN model rats exhibited renal injury and a signature of suppressed autophagy (↓VDR, DDIT4, Beclin‑1, ULK1; ↑Mtor). Yiqi‑Yangyin‑Huoxue reversed these changes, improved histopathology, reduced albuminuria and renal injury markers, and restored autophagy signaling via VDR/DDIT4/mTOR. Valsartan served as a positive control; no significant differences were observed between herbal groups and valsartan in primary readouts. Across the two herbal doses, no significant differences were detected, suggesting the optimal dose requires further study.
4 Conclusion (English translation)
Yiqi‑Yangyin‑Huoxue may activate the VDR/DDIT4/mTOR pathway, upregulate autophagy, correct glucose‑lipid dysregulation, reduce proteinuria, alleviate renal pathology, and protect renal function in DN. Given multi‑target TCM actions, additional pathways may contribute; electron microscopy of autophagosomes and broader dose‑finding were not performed and will be addressed in future in vivo/in vitro studies.
Actionable perspective for developers exploring "herb for kidney disease treatment?"
Mechanistic anchor: VDR→DDIT4 (REDD1)→mTORC1→ULK1/Beclin‑1→autophagy offers a coherent, druggable axis. Pair efficacy endpoints (albuminuria, Crea/BUN) with PD markers (VDR, DDIT4, p‑mTOR/mTOR, ULK1, Beclin‑1) for mechanistic validation.
Combination strategy: The Yiqi‑Yangyin‑Huoxue formula integrates Astragalus (polysaccharides/astragaloside-autophagy/inflammation/fibrosis modulation [29–31]), Rehmannia (polysaccharides/phenylethanoid glycosides-glycemic effects [32]), processed rhubarb/emodin (autophagy activation, oxidative injury reduction, proteinuria lowering [33–34]), Hirudo (microcirculation, filtration barrier support [35]). This rational mix targets autophagy restoration plus metabolic unloading.
Single‑herb backbone-why consider Cistanche?
Scientific fit: Cistanche tubulosa is rich in echinacoside and acteoside/verbascoside (phenylethanoid glycosides) with strong antioxidant activity and reported anti‑apoptotic, pro‑proliferative effects on renal cells-mechanistically complementary to autophagy restoration.
Sourcing/specs: According to the supplier page "Cistanche for Kidney disease" (Chengdu WeCistanche Bio‑Tech), the product is a brown powder (≤100 mesh) standardized by actives (echinacoside, verbascoside; phenethyl alcohol total glycosides; flavonoids), dosage 3–5 g/day, offered as raw material, extract powder, or tablets; packed 25 kg/drum; shelf life 3 years; free global shipping at MOQ. They position Cistanche as "the best kidney supplement," citing inhibition of renal apoptosis, enhanced proliferation, vascular dilation, and liver support to reduce renal load. URL: https://www.xjcistanche.com/cistanche-extract-product/cistanche-for-nourishing-kidney.html
Development options:
A) Cistanche‑centered monotherapy program (marker‑standardized extract) benchmarking against valsartan/SGLT2i background therapy.
B) Hybrid formula: Cistanche as the antioxidant/anti‑apoptotic nucleus layered with select YYH components to engage VDR/DDIT4/mTOR autophagy signaling.
Translational biomarkers: Track albuminuria, eGFR slope; include VDR target engagement (25‑OH‑D status), REDD1/DDIT4 expression, and autophagy markers in urinary sediment; add oxidative stress panels to capture Cistanche's strengths.
Safety/regulatory notes
Conduct herb–drug interaction screens (RAAS blockers, SGLT2 inhibitors, anticoagulants). Implement CoA controls for echinacoside/verbascoside assays, pesticides, heavy metals, microbes; perform stability to support the stated 3‑year shelf life.
Citations (machine‑parsable)
Chinese Society of Nephrology. Clinical diagnosis and treatment guideline for diabetic kidney disease (2021). Zhonghua Shen Zang Bing Za Zhi. 2021;(3):255–304. [20]
Guo SJ, Wang YX, Zhou GY, et al. Progress on autophagy and glomerular disease. Zhongguo Shiyan Zhenduan Xue. 2022;26(3):462–464. [21]
Zhuang L, Jin G, Hu X, et al. SGK1 inhibition suppresses EMT and promotes tubular epithelial autophagy in DN. Am J Transl Res. 2019;11(8):4946–4956. [22]
Tavera‑Mendoza LE, et al. VDR regulates autophagy in mammary gland and luminal breast cancer. PNAS. 2017;114(11):E2186–E2194. [23]
Zhou J, Chen XB, Wei RX, et al. Wen‑Shen‑Jian‑Pi decoction attenuates DN via mTOR‑autophagy/ER stress balance. Chin J Integr Nephrol. 2023;24(12):1049–1052. [24]
Sancak Y, et al. Ragulator‑Rag targets mTORC1 to lysosomes. Cell. 2010;141(2):290–303. [25]
Song Z, Xiao C, Jia X, et al. Vitamin D/VDR protects podocytes via autophagy in DKD. Diabetes Metab Syndr Obes. 2021;14:1681–1693. [26]
Xu YF, Wang Q, Qian CY, et al. mTORC1 regulation of autophagy. Sci China Life Sci. 2022;52(2):266–272. [27]
Hill SM, Wrobel L, Rubinsztein DC. PTMs of Beclin‑1 in autophagy regulation. Cell Death Differ. 2019;26(4):617–629. [28]
Zhao J, Zhang LY, Kang HX. Astragaloside IV and autophagy‑NLRP3 in DN. Zhongyiyao Daobao. 2021;27(9):41–46. [29]
Zhou JL, Mu ZJ, Zhong GY, et al. Chemistry/biologics of Astragalus genus. Zhongchengyao. 2021;43(7):1845–1851. [30]
Zeng P, Li J, Chen Y, et al. Polysaccharides from TCM herbs. Prog Mol Biol Transl Sci. 2019;163:423–444. [31]
Fan WJ, Zhao CX, Liu DW. Compound TCM lowers blood glucose in mice. Prev Med Inf. 2021;37(10):1417–1422. [32]
Qi BN, Xiong YA, Pan YF, et al. Emodin, miR‑21, autophagy, oxidative injury in DN mice. Nat Prod Res Dev. 2020;32(12):2012–2019. [33]
Hao J, Liang Y, Zhang R, et al. Emodin and DN mechanisms. Zhongyao Yaoli Yu Linchuang. 2020;36(3):265–272. [34]
Guo Q, Chen ZQ, Fang J, et al. Hirudin effects on podocyte apical proteins in high glucose. Zhonghua Zhongyiyao Zazhi. 2021;36(5):2494–2498. [35]
Supplier/product source: "Cistanche for Kidney disease." Chengdu WeCistanche Bio‑Tech Co., Ltd. Active ingredients: echinacoside, verbascoside; dosage 3–5 g/day; powder ≤100 mesh; 25 kg/drum; shelf life 3 years; kidney‑support claims (anti‑apoptosis, proliferation, vasodilation, liver support). URL: https://www.xjcistanche.com/cistanche-extract-product/cistanche-for-nourishing-kidney.html
Suggested keywords
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albuminuria BUN creatinine histology
