Abstract: SA-PO1083

Podocyte Injury Enhances Intrarenal Angiotensin II Generation and Sodium Retention Dependently on Megalin

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Koizumi, Masahiro, Tokai University School of Medicine, Isehara, Japan
  • Niimura, Fumio, Tokai University School of Medicine, Isehara, Japan
  • Nishiyama, Akira, Kagawa University Medical School, Kita-Gun, Japan
  • Yanagita, Motoko, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, Japan
  • Matsusaka, Taiji, Tokai University School of Medicine, Isehara, Japan
Background

We have previously shown that podocyte injury enhances glomerular filtration of liver-derived angiotensinogen (Agt) and intrarenal angiotensin (A) II generation (KI 2014) and that filtered Agt is reabsorbed by proximal tubular cells dependently on megalin (JASN 2012). In the present study, we aimed to study the role of megalin in generation of renal AII and sodium handling during nephrotic syndrome.

Methods

We generated proximal tubule-specific megalin knock out (KO) mice by crossing megalin-loxP, Ndrg-Cre, and Kap-Cre mice. Furthermore, to induce podocyte injury, we crossed these megalin KO mice and NEP25 mice, in which podocyte-specific injury can be induced by injection with immunotoxin.

Results

At baseline without podocyte injury, renal Agt staining was markedly diminished, with increase in urinary Agt in KO mice. However, renal AII levels were similar between KO (n=12) and control (n=16) mice (108 ± 11 vs. 101 ± 17 fmol/g tissue). We next tested the effect of megalin KO on AII generation in the kidney with abnormally increased filtered load of Agt in mice with podocyte-specific injury. Control NEP25 mice (n=10) showed markedly intense renal Agt staining and enhanced renal AII levels (450 ± 61 fmol/g tissue) 7 days after the induction of podocyte injury. Megalin KO/NEP25 mice (n=12) showed diminished renal Agt staining and significantly attenuated renal AII levels (119 ± 23 fmol/g tissue, p < 0.01).
Compared with control NEP25 mice, megalin KO/NEP25 mice excreted more sodium in urine (U-Na/Cr: 2.06 ± 0.83 vs. 0.58 ± 0.26, p < 0.001). Four days after the induction of podocyte injury, when tubulointerstitial damage is milder, the result was comparable. Blood pressure levels were similar between the two groups. Quantitative RT-PCR showed that NKCC2 mRNA in megalin KO/NEP25 mice were 70.6% to that of control (p < 0.01).

Conclusion

These indicate that, in podocyte injury, abnormally increased filtered load of Agt is reabsorbed via megalin by proximal tubular cells and induces the inappropriate activation of intrarenal renin-angiotensin system, which may contribute to sodium retention and edema formation.

Funding

  • Government Support - Non-U.S.