BPC-157 in the genitourinary system. Peptide therapy for kidney disease.

Abstract: The action of BPC-157 in the urogenital system is involved both in preventive and nephroprotective treatment and also contributes to the alleviation of already existing pathological conditions and the mitigation of their symptoms.

Keywords: urinary system; reproductive system; urogenital system; kidney; ureter; urinary bladder; pelvis; uterus; rectum; urethra; nephrolithiasis; vesicovaginal fistula; megaureter; urinary incontinence; BPC-157 peptide therapy; experimental studies; method; ureteral stricture; scrotal injury; nephroprotection; disease

List of abbreviations: BPC-157 – Body Protection Compound; LPP – Leak Point Pressure – intravesical pressure value

Material and methods: The studies were conducted on laboratory animals, in this case male and female albino rats.

Urogenital system

Structure of the urogenital system

The most important components of the urinary system are the kidneys, which are paired organs whose parenchyma is composed of nephrons. Due to their rich vascularisation, each kidney is supplied by a renal artery, which branches into upper, middle and lower segments.

The kidneys are made up of the medulla and cortex, from which the papillae project into the minor calyces and then into the renal pelvises, forming the next element of the system – the ureters. The ureters connect the kidneys with the urinary bladder, which is a reservoir located in the pelvis. Posteriorly, it is related to the pubic symphysis, while its anterior relations differ depending on sex. In the female urogenital system, the uterus is located anteriorly to the bladder, whereas in the male system this position is occupied by the rectum.

Urine accumulated in the urinary bladder is excreted through the urethra, which is longer in males than in females. In both sexes, the urethra is connected with the genital organs, which gives rise to the urogenital system. The structure of the urinary system also includes interlobar arteries that continue as arcuate arteries. For illustration, the structure of the female and male urogenital system is shown schematically below (Fig. 1).

Figure 1. Structure of the male and female urogenital system

Functions of the urogenital system

The primary function of the urinary system is the excretion from the body of all unnecessary and harmful products of metabolism, which is why it may also be referred to as the excretory system. In addition, it participates in hormone production and maintains a constant level of body fluids.

The fundamental function of the reproductive (genital) system is reproduction through the production of gametes and oocytes. The male reproductive organs primarily serve to produce semen containing spermatozoa, whereas the female organs produce oocytes and hormones and also provide the conditions for fertilisation and fetal development within the maternal organism.

Diseases of the urogenital system

The human urogenital system is particularly sensitive and susceptible to infections, which is why prevention of diseases of this system is so important. Untreated urogenital diseases may lead to serious consequences and complications such as infertility and, in extreme cases, may even be life-threatening.

To avoid disease processes and prevent their exacerbation, regular basic urinalysis and preventive therapies are essential. Such measures protect the urogenital system against various infections and diseases, all the more so because these conditions often lack early symptoms, which hampers diagnosis and delays treatment.

A modern method in the management of disorders and diseases of the urogenital system is BPC-157 therapy. Some of the diseases influenced by peptide therapy are presented in the table below (Tab. 1).

Table 1. Examples of human urogenital diseases

BPC-157 peptide therapy in selected disorders of the urogenital system

1. Urinary incontinence

Urinary incontinence is defined as the condition in which urine leakage is uncontrolled and involuntary, e.g. during coughing, sneezing or physical exertion. In general classification, several degrees of urinary incontinence are distinguished, depending on the volume of uncontrolled urine leakage: dribbling, mild, moderate, severe and very severe.

The most common cause of urinary incontinence is considered to be weakening of the pelvic floor muscles, which are responsible for closing the urethra and controlling urination. Symptoms occur in both women and men; however, in women they are more frequent due to pelvic surgeries and procedures, vaginal deliveries and hormonal changes. In men, urinary incontinence most commonly develops as a result of prostatic enlargement.

The condition may coexist with other diseases such as diabetes, Ehlers-Danlos syndrome or chronic constipation. Pharmacological treatment is used primarily in urge incontinence and involves anticholinergic drugs. Surgical treatment is most often applied in stress urinary incontinence, for example by implanting an artificial sphincter. Conservative management may include pelvic floor muscle electrostimulation or Kegel exercises.

Currently, BPC-157 therapy significantly improves the condition of these muscles, which in turn reduces the risk of symptom occurrence and alleviates them.

a. BPC-157 peptide therapy

Due to its profile of action, BPC-157 acts as a tissue-pliability-enhancing agent, leading to strengthening of the pelvic floor muscles. As is known from previous articles, the peptide also exerts effects on the nervous system, which in the case of urinary incontinence results in suppression of the sensation of urgency.

Regular, preventive use of BPC-157 peptide leads to thickening of the muscular structure of the urethra, which translates into a markedly reduced risk of urinary incontinence in the future. Use of BPC-157 therapy can lead to complete resolution of urinary incontinence. (Fig. 2)

Figure 2. BPC-157 peptide therapy in urinary incontinence

b. Experimental studies

Material
Female albino rats weighing 310–350 g were used for the study.

Study protocol
The procedure was performed under deep anaesthesia with intraperitoneally administered ketamine. Sharp dissection of the endopelvic fascia was carried out, resulting in peripheral separation of the proximal and distal urethra from the anterior vaginal wall and the pubic bone.

After the procedure, the control group received saline and a catheter was inserted. In the test group, BPC-157 peptide was administered for seven days following the procedure. During the study, the occurrence of bladder contractions and leakage from the bladder was monitored by filling the bladder while applying pressure to induce fluid release at the urethral orifice.

After completion of measurements, the entire bladder and urethra were excised by removing the pubic symphysis, thereby preserving the entire urethral segment. Changes within this segment were assessed using specialised computer software connected to a microscope.

Results

BPC-157 peptide therapy, irrespective of the dosing regimen or route of administration, completely prevented the decrease in LPP (Leak Point Pressure), that is, intravesical pressure. Due to the action of BPC-157, baseline values recorded in healthy rats were restored. In addition, the urethral wall treated with BPC-157 displayed a thicker and more regular muscular structure, whereas the control group showed the presence of a thin muscle layer. (Fig. 3)

Figure 3. Urethral wall during BPC-157 therapy (A) and in the control group (B)

Conclusions

The above results indicate that, compared with controls, BPC-157 exerts a regenerative effect on urethral damage and, when used in conservative treatment, reduces the likelihood of urinary incontinence symptoms.

2. Vesicovaginal fistula

A vesicovaginal fistula is a condition very often confused with urinary incontinence mentioned above. The fistula develops as a result of damage to the thin wall of the urinary bladder, which due to its anatomical structure lies adjacent to the vagina. The most common cause of the condition is considered to be complications following gynaecological procedures.

Other causes include caesarean section, radiotherapy to the bladder or foci of endometriosis. Depending on fistula size, vesicovaginal fistulas may be classified as simple or complex.

Symptoms of fistula formation include the passage of urine into the vagina accompanied by abdominal pain, intestinal obstruction and haematuria. In acute and complex cases, treatment is usually surgical. In adjuvant, regenerative or preventive therapy, BPC-157 peptide is used.

a. BPC-157 peptide therapy

In light of the studies cited below, BPC-157 therapy represents a safe peptide profile administered parenterally or orally in patients with vesicovaginal fistulas. Under appropriate conditions, it may be one of the options in the process of post-fistula wound healing.

Vesicovaginal fistulas are associated with recurrent intimate infections, discomfort and progressive social withdrawal of patients, which is why it is so important to choose an appropriate and safe therapy such as BPC-157. As an adjunct to surgical treatment, BPC-157 participates in postoperative regeneration of vesicovaginal fistulas. In preventive and regenerative treatment of simple cases, it may prevent the development and recurrence of this condition and also contribute to its resolution.

b. Experimental studies

Material
Female rats weighing 200 g and aged 8–10 weeks were used in the study.

Study protocol
The procedure was performed under deep anaesthesia with intraperitoneally administered ketamine. A longitudinal incision 4 mm in length was made in the posterior bladder wall and anterior vaginal wall, creating a vesicovaginal fistula using a single-layer technique with individual sutures.

BPC-157 was administered at doses of 10 μg/kg, 1 μg/kg, 100 ng/kg and 10 ng/kg throughout the study, i.e. on day 0, when therapy was initiated, and daily during the experimental period at 7, 14, 21, 28 and 42 days. Control animals received an equivalent volume of saline.

Immediately before euthanasia, under deep anaesthesia, the pressure of fluid required to induce fistula leakage was measured (biomechanical assessment). Differences in fistula healing between groups were assessed microscopically. During the study, the presence of urine in the vagina, possible urinary incontinence and the macroscopic appearance of the vagina and urethra were monitored daily. After euthanasia, the presence of adhesions, signs of infection and healing of fistula tissue on the bladder and vaginal sides were evaluated.

Results

Following administration of BPC-157 at all doses (10 μg/kg, 1 μg/kg, 100 ng/kg and 10 ng/kg), particularly 14 days after surgery, the diameter of the fistula orifice was significantly reduced. Complete closure of the vesicovaginal fistula occurred in all rats treated with BPC-157 after six weeks of peptide therapy.

In addition, no urinary stones were found in the treated group. In contrast, in control animals, urinary calculi and vesicovaginal fistulas were present. Histological examination demonstrated marked collagenisation and neovascularisation leading to closure of the tissue defect and reduction of inflammation under the influence of BPC-157. (Fig. 4)

Figure 4. Histological image of a markedly reduced vesicovaginal fistula following BPC-157 administration

Conclusions

Through the action of BPC-157 at doses of 10 μg/kg, 1 μg/kg, 100 ng/kg and 10 ng/kg, vesicovaginal fistulas in rats were healed, indicating that BPC-157 exerts a potent protective effect by alleviating tissue damage and structural abnormalities caused by injury.

3. Ureteral stricture

Ureteral stricture, also referred to as ureteropelvic junction obstruction, is a condition consisting of a defect of the ureter that leads to retention/stasis of urine proximal to the narrowing. The normal flow of urine from the kidneys to the bladder via the ureter is impeded.

This process results in urine retention within the kidney, with a concomitant increase in intrarenal pressure, parenchymal damage and renal failure leading to hydronephrosis. The causes of ureteral stricture include congenital abnormalities of smooth muscle in the ureteral wall, abnormal ureteral vascularisation, fibrous adhesions or vesicoureteral reflux.

Hydronephrosis may occur in one or both kidneys, and depending on this, the symptoms differ. If hydronephrosis affects one kidney, symptoms include lumbar pain, vomiting, nausea and a positive Goldflam’s sign. Bilateral hydronephrosis is characterised by loss of appetite, weight gain, oedema of both lower limbs, weakness and nausea.

In acute and severe cases, surgical treatment is indicated. In milder courses, ureteral stricture may be managed with specialised drugs and BPC-157 as a novel therapeutic option.

a. BPC-157 therapy

BPC-157 peptide therapy promotes correct ureteral function. The flow of urine produced by the kidneys to the bladder through the ureter is restored. Through the action of BPC-157, intrarenal pressure is reduced, which significantly improves kidney condition and function. Hydronephrosis that develops in the course of ureteral stricture is halted or eliminated under the influence of the peptide.

In preventive treatment, BPC-157 therapy reduces the risk of ureteral stricture in the future.

b. Experimental studies

Material
Male rats were used in the study.

Study protocol
In rats, ureteral ligation was performed, which led to hydronephrosis, development of fibrosis, tubular cell damage and interstitial inflammation. After injury induction, BPC-157 peptide was administered intraperitoneally at doses of 10 μg/kg and 10 ng/kg. In the control group, an equivalent volume of saline was used.

Outcome assessment was performed 24 and 96 hours after peptide administration and included evaluation of renal changes on a scale from 0 to 3, where:
0 – healthy kidney,
1 – mild hydronephrosis,
2 – moderate hydronephrosis, evident dilatation of renal pelvises, few surface changes,
3 – severe hydronephrosis, pelvic dilatation, cortical thinning and numerous surface lesions.

Results

The action of BPC-157 peptide led to a clear and advanced improvement in ureteral condition, observed at both 24 and 96 hours. Persistent severe hydronephrosis, pelvic dilatation and cortical thinning were halted. Acute hydronephrosis reverted to mild hydronephrosis or was completely absent.

Conclusions

The action of BPC-157 at doses of 10 μg/kg and 10 ng/kg eliminates hydronephrosis, increased intrarenal pressure and renal failure, thereby halting the course of ureteral stricture.

4. Scrotal injury

Scrotal injury belongs to the group of blunt traumas resulting from contusion, occupational accidents, injuries sustained in incidents or assaults, or during certain sports. Injuries may be classified as open or closed. Open injuries occur when the continuity of scrotal skin is disrupted. In isolated scrotal injury, skin loss is most commonly observed. Closed injuries may present with oedema, tenderness and bruising.

In the presence of scrotal skin defects, coverage with skin grafts from the perineal or thigh region is possible. In the case of contusions and mild scrotal injuries, regenerative pharmacotherapy is implemented, including BPC-157 peptide therapy.

a. BPC-157 therapy

BPC-157 exhibits a strong, beneficial and regenerative effect on scrotal oedema, which is significantly reduced under the influence of the peptide. Regular use of BPC-157 leads to alleviation of pain and swelling associated with scrotal injury.

Treatment with BPC-157 is characterised by high efficacy and a favourable safety profile and additionally prevents the progression and enlargement of scrotal injuries and oedema.

5. Cystitis (bladder inflammation)

Cystitis is defined as a urinary tract infection caused by microorganisms that may proliferate, leading to inflammation. Under physiological conditions, the urinary tract proximal to the bladder sphincter is sterile.

The bacterial pathogen responsible for most cases of cystitis is Escherichia coli (E. coli). This bacterium may migrate from the anus to the urethral orifice, then to the bladder, and possibly further to one or both kidneys.

Symptoms of cystitis include pain and burning during urination, increased urinary frequency and pain in the lower abdomen. In addition, urine may become red or dark red, which indicates haematuria resulting from inflammation of the bladder mucosa.

In the initial stage, oral treatment is used, most commonly with furazidine. To alleviate symptoms, analgesics or antispasmodics may also be introduced. In more severe forms and courses of cystitis, an appropriate antibiotic is recommended based on antibiogram results. Currently, BPC-157 peptide therapy is also used in cystitis.

a. BPC-157 therapy

The action of BPC-157 peptide is bacteriostatic, preventing pathogen proliferation. It mobilises the immune system to fight microorganisms in the urinary tract, which leads to elimination of inflammation in the bladder and resolution of cystitis.

Furthermore, BPC-157 may be used in preventive therapy for recurrent cystitis, thus eliminating the development of this condition. (Fig. 5)

Figure 5. BPC-157 peptide therapy in cystitis

Nephroprotective action of BPC-157
Concept of nephroprotection

Nephroprotection can be understood in two ways. Firstly, it refers to the protection of the kidneys both in disease, when nephroprotective measures prevent symptom exacerbation, and in health, when they prevent the development of renal diseases and disorders.

In the context of nephrology, nephroprotection concerns the planning of both implementation and withdrawal of drugs and procedures aimed at protecting healthy kidneys and alleviating symptoms in diseased kidneys.

With regard to the concept of nephroprotection, we may refer to the action profile of modern BPC-157 peptide therapy. BPC-157 peptide shows both preventive and symptom-alleviating nephroprotective effects.

Nephroprotective BPC-157 therapy

The nephroprotective effect of the BPC-157 peptide has been illustrated using the example of cisplatin-induced nephrotoxicity; cisplatin is a drug used in chemotherapy. Although the peptide cannot be used during cancer treatment, its nephroprotective action can be demonstrated using this example of how destructive such therapy can be to the kidneys.

By analogy, in the context of drugs with milder effects and various types of renal damage, BPC-157 will be even more effective and safe. BPC-157 peptide therapy, which exhibits a nephroprotective effect, reduces proteinuria while preserving glomerular filtration function as a result of simultaneous dilation of afferent and efferent arterioles. Consequently, there is no increase in intraglomerular pressure and no disturbance of glomerular autoregulation.

These processes together constitute the nephroprotective action of the BPC-157 peptide.

References

1. Jandric I., Balen M., Vrcic H. Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats. 2013; 19: 93–102; DOI: 10.12659/MSMBR.883828 (Received: 2011.12.30; Accepted: 2012.07.26; Published: 2013.03.12).
2. Blagaić A., Sever M. Effect of pentadecapeptide BPC 157 on healing of vesicovaginal fistula in rats. 2021; 11:53:12.
3. Sven Seiwerth, Marija Milavić, Jaksa Vukojević. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. 2021; DOI: 10.3389/fphar.2021.627533.
4. Kopjar I., Milić N., Sirovina M., Miše D. Protective and Reparative Effect of Pentadecapeptide BPC 157 on Mice Blood, Liver and Kidney Cells. Gastroenterology. 2012; 142(5): 451; doi:10.1016/S0016-5085(12)61701-6.