Nephronprotective Effects of Curcumin and Piperine in Lipopolysaccharide-Induced Systemic Inflammation in Wistar Rats

Systemic inflammation is a pathological condition characterized by widespread activation of the immune system and production of inflammatory mediators. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, is widely used to induce systemic inflammation in animal models due to its ability to mimic sepsis-like conditions [1]. The kidneys, being highly vascularized organs, are particularly susceptible to damage under systemic inflammatory conditions, leading to acute kidney injury (AKI). Sepsis-induced AKI remains a major clinical challenge, often resulting from systemic inflammation caused by bacterial endotoxins such as LPS. The kidneys are particularly vulnerable due to their high perfusion and metabolic activity [2]. Curcumin, a polyphenol from turmeric, and piperine, an alkaloid from black pepper, possess strong anti-inflammatory and antioxidant activities [3,4]. However, curcumin’s poor bioavailability limits its clinical potential. Piperine, an alkaloid from Piper nigrum, has been shown to enhance the bioavailability of curcumin by inhibiting hepatic and intestinal glucuronidation [4]. The combination of curcumin and piperine may synergistically improve the management of inflammation-induced nephropathy. This study investigates the protective role of curcumin and piperine against LPS-induced renal inflammation, oxidative damage, and histopathological alterations in Wistar rats.

AKI remains a critical complication of systemic inflammatory states, particularly sepsis. LPS, a component of Gram-negative bacterial walls, induces systemic inflammation in experimental models, mimicking human septic responses [1,2]. The kidneys, due to their extensive vasculature and metabolic demands, are particularly vulnerable to oxidative and inflammatory damage initiated by LPS exposure [2]. Curcumin and piperine, natural phytocompounds known for their anti-inflammatory and antioxidant attributes, have gained attention for their potential in ameliorating LPS-induced nephrotoxicity [3–5]. Notably, piperine enhances the bioavailability of curcumin, making their combination a synergistic therapeutic strategy [4]. This review explores the mechanisms by which curcumin and piperine confer renal protection in LPS-induced systemic inflammation using Wistar rat models.

1.1  Pathophysiology of LPS-Induced AKI

LPS triggers renal inflammation by binding to Toll-like receptor 4 (TLR4) expressed on renal tubular and endothelial cells. This interaction activates nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), leading to elevated expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [6]. These mediators increase vascular permeability, promote leukocyte recruitment, and lead to hypoperfusion and ischemia, ultimately causing tubular damage and interstitial inflammation [7,8].

Figure 1. Schematic illustration of TLR4-mediated LPS signaling pathways in renal tissue.

Figure 2: Experimental Procedures

Table 1: Weight Changes across Groups

Group	Initial Weight (g)	Final Weight (g)	Weight Change (g)
Control	250 ± 5	280 ± 6	+30 ± 3
Curcumin	248 ± 6	278 ± 5	+30 ± 4
Curcumin + Piperine	249 ± 5	277 ± 6	+28 ± 4
LPS	252 ± 5	230 ± 7*	-22 ± 5 #
Curcumin + Piperine + LPS	250 ± 6	255 ± 6*	+5 ± 3#
LPS + Curcumin + Piperine	251 ± 5	258 ± 7	+7 ± 4
LPS Recovery	253 ± 6	260 ± 7	+7 ± 3

Figure 3: Weight change graph

Table 2: Biochemical Markers in Serum and Renal Tissue

Group	Creatinine (mg/dL)	Urea (mg/dL)	MDA (nmol/mg)	SOD (U/mg)	GSH (µmol/g)
Control	0.65 ± 0.08	32.1 ± 3.4	2.5 ± 0.3	8.0 ± 0.5	6.5 ± 0.4
LPS	1.80 ± 0.12*	58.2 ± 4.5*	6.2 ± 0.4*	4.5 ± 0.3*	3.0 ± 0.2*
Curcumin + LPS	1.10 ± 0.10*	40.8 ± 3.2*	3.8 ± 0.3*	6.2 ± 0.4*	5.0 ± 0.3*
Curcumin + Piperine + LPS	0.90 ± 0.09	35.6 ± 3.0	3.1 ± 0.2	7.0 ± 0.3	5.8 ± 0.2

 

 

Figure 4a: Biochemical Evidence

        

 

              

SOD,GSH and CAT levels were depleted in LPS groups but improved with curcumin treatment. Curcumin + Piperine combination showed the most significant antioxidant effect. LPS significantly increased MDA level but was in turn significantly reduced by curcumin/piperine treatment. Curcumin + Piperine combination showed the most significant antioxidant effect

          

 

Figure 4b: Cytokine Modulation

         

IL-10 and IL-13 levels were higher in curcumin-treated groups, indicating potential immunomodulation.

Table 3: Semi-Quantitative Histological Scores of Renal Tissue

Group	Tubular Damage	Glomerular Alteration	Inflammation	Fibrosis
Control	0	0	0	0
LPS	3	3	3	3
Curcumin + LPS	1	1	1	1
Cur + Pip + LPS	0–1	0–1	0–1	0–1

       

        

 

         Control Grp                                            LPS Grp                                 Curcumin/Piperine Grp

Figure 5a. Histopathological comparison of renal tissue micrograph in control, LPS, and curcumin-treated groups (H&E staining).

       

       

 

 

                   Control Grp                                         LPS Grp                                  Curcumin/Piperine Grp

Figure 5b. Comparative photomicrographs showing collagen deposition in renal tissue (Masson’s Trichrome). Micrograph of the Kidney sections.

There was Normal renal histology  with minimal collagen in interstitium. Extensive collagen around glomeruli Interstitial fibrosis in LPS treated group. While the preventive treated  group Significantly reduced collagen intensity.

4. DISCUSSION

The present study demonstrates that curcumin and piperine offer significant nephronprotective effects in LPS-induced systemic inflammation. These findings align with previous reports demonstrating their ability to modulate oxidative stress and inflammatory pathways. Our results support the nephronprotective effects of curcumin and piperine in LPS-induced AKI. Biochemical parameters confirmed restoration of renal function, oxidative balance, and anti-inflammatory activity. Histologically, the co-treatment group exhibited minimal tissue injury and collagen deposition. The bioavailability-enhancing role of piperine likely potentiated the effects of curcumin, allowing for more efficient cellular uptake and anti-inflammatory action. Moreover, their antioxidant properties contributed to reducing lipid peroxidation and restoring redox balance. Histologically, the preservation of renal microarchitecture and reduced collagen deposition further support the efficacy of this combination therapy. The enhancement of curcumin's efficacy by piperine further supports their combined use as a potential therapeutic approach

Changes in body weight observed across the experimental groups highlight the physiological consequences of systemic inflammation and the modulatory roles of curcumin and piperine. The control group demonstrated consistent weight gain, reflective of normal physiological growth under non-inflammatory conditions [3]. Similarly, groups treated with curcumin or the curcumin–piperine combination without lipopolysaccharide (LPS) exposure showed comparable weight increases, suggesting that these phytochemicals do not negatively affect body weight or general health [4]. In contrast, rats administered LPS alone exhibited a marked reduction in body weight, indicating the catabolic burden imposed by systemic inflammation [17].

4.1 Biochemical Analysis

LPS administration resulted in a significant elevation in serum creatinine and urea levels, confirming the onset of acute kidney injury (AKI). These increases reflect a compromise in glomerular filtration due to systemic inflammation.These biochemical changes are consistent with acute kidney injury (AKI), often observed in systemic inflammatory response syndrome and sepsis models [18,19].  In contrast, rats treated with curcumin and the curcumin-piperine combination displayed markedly lower levels of these markers, indicating preserved renal function. Oxidative stress markers further supported this trend. The LPS group exhibited significantly elevated malondialdehyde (MDA), a lipid peroxidation product, alongside reduced antioxidant enzymes such as superoxide dismutase (SOD) and glutathione (GSH). Treatment with curcumin alone, and more effectively with piperine co-administration, restored antioxidant status—demonstrating the compounds' free radical scavenging capabilities. This aligns with earlier findings that curcumin modulates oxidative pathways and enhances redox homeostasis.

4.2 Cytokine Modulation and Anti-inflammatory Effects

Inflammatory cytokine profiling revealed substantial upregulation of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in the LPS group. These cytokines are well-known mediators of sepsis-related tissue injury. Conversely, animals treated with curcumin and piperine exhibited a significant reduction in these pro-inflammatory markers and an increase in interleukin-10 (IL-10), an anti-inflammatory cytokine. These results suggest that curcumin and piperine exert a modulatory effect on the immune response, likely through inhibition of NF-κB signaling. These findings align with prior research demonstrating that curcumin ameliorates LPS-induced nephrotoxicity through modulation of NF-κB pathways, reduction in oxidative stress, and attenuation of inflammatory cytokines such as TNF-α and IL-1β [20].

4.3 Histopathological Observations

Histological sections from control animals showed normal renal architecture with intact glomeruli and tubules. LPS exposure caused severe tubular necrosis, glomerular collapse, and interstitial infiltration, hallmarks of endotoxin-induced renal injury. Remarkably, co-treatment with curcumin and piperine attenuated these lesions, preserving tissue integrity. The combination therapy was more effective than curcumin alone, reflecting piperine's bioenhancement properties.

Masson’s Trichrome staining revealed extensive collagen deposition and fibrosis in LPS-only kidneys. In treated groups, particularly those receiving both curcumin and piperine, collagen accumulation was significantly reduced, indicating anti-fibrotic effects. This supports previous evidence suggesting that curcumin interferes with fibrogenic signaling cascades such as TGF-β. The histopathological preservation observed in our study further corroborates curcumin’s renoprotective effects, especially when co-administered with piperine [21].

4.4 Integrative Interpretation

The combination of biochemical, immunological, and histological results underscores the nephronprotective efficacy of curcumin and piperine in LPS-induced systemic inflammation. Their antioxidant and anti-inflammatory properties synergize to maintain renal architecture and function. Moreover, the enhanced efficacy of the combination treatment highlights the pharmacokinetic benefit of co-administering piperine with curcumin, as the latter has limited bioavailability when administered alone.

These findings are consistent with the hypothesis that curcumin-piperine co-treatment mitigates endotoxemia-induced nephropathy through a multifaceted mechanism involving suppression of oxidative stress, inhibition of pro-inflammatory cytokine release, and preservation of tissue integrity.

CONCLUSION

Curcumin and piperine exhibit significant nephronprotective effects in a rat model of LPS-induced systemic inflammation. Their combined use attenuates renal dysfunction, oxidative stress, and histopathological damage. These findings suggest the therapeutic potential of curcumin-piperine co-administration in inflammatory renal disorders.

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