Dissociation of Hypertension and Renal Damage After Salt Cessation in Dahl Rats . Lovely professional University

Dissociation of Hypertension and Renal Damage After Salt Cessation in Dahl Rats . Lovely professional University

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  Dissociation of Hypertension andRenal Damage after Salt Cessation in Dahl Rats Presented by Kaif Sekh
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  Contents • Introduction • Rationale •Novelty • Method • Results • Discussion • Limitations • References
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  Introduction • 1.4 billionpeople globally suffer from hypertension (WHO). • Salt-sensitive hypertension (SSH) is a major contributor. • Even when patients reduce their salt intake, their high blood pressure (hypertension) does not go back to normal or remains elevated.
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  Rationale To identify effectsof salt-induced hypertension are reversible or irreversible. To understand why hypertension persists in some individuals even after salt reduction. To assess the role of ENaC in maintaining high blood pressure after salt withdrawal. To evaluate whether immune cell (T-cell) infiltration in kidneys reverses after salt restriction. 01 02 03 04
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  Novelty  Blood pressurestays high even after eating less salt.  kidney channel (ENaC) keeps working too much and raises pressure.  Immune cells in the kidney go back to normal after salt is reduced.  Some kidney problems get better, but some stay.
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  Methodology Species Used: MaleDahl salt-sensitive (SS) rats. Source: Bred for over 15 generations at Henry Ford Health (originally from Medical College of Wisconsin). Ethics: Experiments followed ARRIVE guidelines and were approved by IACUC. 🧪 Housing and Maintenance Environment: 12-hour light/dark cycle. Diet: Standard chow with 0.4% NaCl . Access: Water and food provided.
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  🧪 Protocol 1:Salt Challenge and BP Monitoring Purpose: Test sensitivity of post-salt hypertension to ENaC inhibition.
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  🧪 Protocol 2:Salt Challenge & Kidney Analysis Urine Analysis: ◦ 24-hour urine samples collected before diet switch ◦ Measured sodium and chloride excretion using a Carelyte analyzer
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  🧪 Protocol 3:Kidney Analysis Without Telemeters  No telemeters used  3 groups of rats (N = 5–8 per group)  Control Group: • Normal salt diet (0.4% NaCl) from week 9 to 16  High Salt Group: • High salt diet (4% NaCl) from week 12 to 16  Salt Withdrawal Group:  High salt diet for 4 weeks (weeks 9–13)  Then normal salt diet for 3 weeks (weeks 13–16) At Week 16: Kidneys collected for:  Flow cytometry (immune cells)  Histology (tissue damage)
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  🧪 Protocol 4:Low–High–Low Salt Cycle with Telemetry N = 4 rats with implanted telemeters 📅 Timeline: Weeks 4–8: ◦ Low salt diet (0.1% NaCl) Weeks 8–12: Switched to High salt diet (4% NaCl) ◦ Goal: Induce hypertension Weeks 12–20: ◦ Switched back to Low salt diet (0.1% NaCl) ◦ Continued for 8 weeks 📈 BP Monitoring: •Blood pressure recorded continuously •Telemetry turned off intermittently to conserve battery
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  • Short-term highsalt raised BP but was reversible. • Long-term high salt caused sustained hypertension, even after stopping salt. • Benzamil temporarily lowered BP by blocking ENaC, but BP rose again after stopping it. • Control rats on normal salt had consistently lower BP. Partial Reversibility of Hypertension - Results
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  Salt Challenge &Kidney Analysis - • Researchers gave rats a high salt diet and checked if a kidney channel called ENaC stayed active after salt was stopped. • They found that even after switching to normal salt, blood pressure stayed high and ENaC activity remained elevated. • This means that ENaC stays overactive even after stopping salt, which may help explain why high blood pressure doesn’t go away.
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  T-cell Infiltration inKidney - • High salt intake increased kidney T-cell levels (CD45+, CD3+, CD4+, CD8+), as measured by flow cytometry. • Switching from high salt to normal salt normalized these immune cell levels. • This shows that T-cell infiltration in kidneys is reversible and mainly driven by salt, not just high blood pressure. • Overall, the salt itself — not just high blood pressure — plays a key role in attracting immune cells to the kidney.
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  Tubular Damage andRecovery - • High salt → protein cast formation (a sign of tubular damage → kidney damage). • Salt reduction → reduced casts and tubular recovery. • Tubular injury is reversible. • The summary graph (D) confirms that salt restriction helps kidney tissue recover by lowering protein cast formation.
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  Low–High–Low Salt - HighSalt Diet (4 weeks) ➤ Switch to Very Low Salt (0.1% NaCl) Blood Pressure Remains High Self-Sustaining Hypertension ➤ Hypertension may not fully reverse, even with strict salt reduction ➤
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  Discussion 1. High SaltIntake → Starts the Problem  Too much salt raises BP.  Activates ENaC, causes kidney stress, and brings immune cells.️ 2. ENaC Stays Overactive → BP Remains High  Even after cutting salt, ENaC stays active.  Benzamil-sensitive → confirms ENaC's role. 3. Kidney Damage → Proteinuria & Poor Filtration  Salt causes tubular damage.  Protein leaks → activates ENaC even more. 4. Immune Cell Infiltration → Inflammation  T-cells & macrophages increase with high salt.  Leads to oxidative stress & worsens injury.  Reducing salt helps reverse T-cell infiltration.
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  5. Salt RestrictionHelps → But Not Fully  Filtration improves, mmune cells reduce.  But proteinuria & some damage remain.
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  Limitations Some problems, likeprotein in urine, stayed even after lowering salt. Not all damage got better The effects were only checked for a few weeks. Long-term results are unknown. Short time study Other causes of high BP were not studied in detail. Only looked at one main pathway(ENaC) Results might be different in female rats or other animals Only male rats used
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  References • WHO GuidelinesApproved by the Guidelines Review Committee. In: Guideline for the pharmacological treatment of hypertension in adults. Geneva: World Health Organization © World Health Organization 2021.; 2021. • Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt Sensitivity, Pulse Pressure, and Death in Normal and Hypertensive Humans. Hypertension. 2001;37:429–432. doi: 10.1161/01.hyp.37.2.429 [PubMed: 11230313] • Johnson C, Raj TS, Trudeau L, Bacon SL, Padwal R, Webster J, Campbell N. The Science of Salt: A Systematic Review of Clinical Salt Studies 2013 to 2014. The Journal of Clinical Hypertension. 2015;17:401–411. doi: 10.1111/jch.12529 [PubMed: 25789451] • Campbell NRC, Whelton PK, Orias M, Wainford RD, Cappuccio FP, Ide N, Neal B, Cohn J, Cobb LK, Webster J, et al. 2022 World Hypertension League, Resolve To Save Lives and International Society of Hypertension dietary sodium (salt) global call to action. Journal of Human Hypertension. 2022. doi: 10.1038/s41371-022-00690-0 Arkhipov et al. Page 10.