Role of connecting tubule glomerular feedback in obesity related renal damage

Abstract

Zucker obese rats (ZOR) have higher glomerular capillary pressure (P_GC) that can cause renal damage. P_GC is controlled by afferent (Af-Art) and efferent arteriole (Ef-Art) resistance. Af-Art resistance is regulated by factors that regulate other arterioles, such as myogenic response. In addition, it is also regulated by 2 intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation, which in turn increases P_GC in ZOR. We performed a renal micropuncture experiment and measured stop-flow pressure (P_SF), which is an indirect measurement of P_GC in ZOR. Maximal TGF response at 40 nl/min was attenuated in ZOR (4.47 ± 0.60 mmHg) in comparison to the Zucker lean rats (ZLR; 8.54 ± 0.73 mmHg, P < 0.05), and CTGF was elevated in ZOR (5.34 ± 0.87 mmHg) compared with ZLR (1.12 ± 1.28 mmHg, P < 0.05). CTGF inhibition with epithelial sodium channel blocker normalized the maximum P_SF change in ZOR indicating that CTGF plays a significant role in TGF attenuation (ZOR, 10.67 ± 1.07 mmHg vs. ZLR, 9.5 ± 1.53 mmHg). We conclude that enhanced CTGF contributes to TGF attenuation in ZOR and potentially contribute to progressive renal damage.

Keywords: CTGF; TGF; obesity; renal damage.

Fig. 1.

Blood pressure and body weight in Zucker rats: A: mean arterial pressure measured during renal micropuncture via intra-femoral arterial catheter under anesthesia was found to be elevated in ZOR compared with the lean controls. B: ZOR weighed significantly higher compared with lean controls. Mean arterial pressure (A) and body weight (B) in ZLR and ZOR. ZLR (open bar) and ZOR (closed bar). n = 11 in ZLR and n = 14 in ZOR group for mean arterial pressure. n = 14 in ZLR group and n = 13 in ZOR for body weight. *P < 0.05, ZOR vs. ZLR. ZLR, Zucker lean rat; ZOR, Zucker obese rat.

Fig. 2.

Time control experiments for both ZLR and ZOR. Increasing perfusion rates in the late proximal tubule 2 consecutive times does not affect P_SF reproducibly (○, first curve; ●, second curve) in both ZLR (A) and ZOR (B). Both curves were generated using the same tubule. n = 6 in each group. P_SF, stop flow pressure; ZLR, Zucker lean rat; ZOR, Zucker obese rat.

Fig. 3.

A: TGF response in ZLR was significantly higher compared with ZOR, indicating TGF attenuation. B: maximum P_SF change in ZLR and ZOR. n = 14 in each group. *P < 0.05, ZLR vs. ZOR. P_SF, stop flow pressure; TGF, tubuloglomerular feedback; ZLR, Zucker lean rat; ZOR, Zucker obese rat.

Fig. 4.

Effect of benzamil on P_SF change in both ZLR (A) and ZOR (B). *P < 0.05, ZOR vehicle vs. ZOR benzamil. n = 6 in ZLR group and n = 7 in ZOR group. P_SF, stop flow pressure; ZLR, Zucker lean rats; ZOR, Zucker obese rats.

Fig. 5.

Comparison of maximum CTGF in both ZLR and ZOR. CTGF is enhanced in ZOR (black bar) compared with ZLR (open bar). n = 6 in ZLR group and n = 7 in ZOR group. *P < 0.05, ZLR vs. ZOR. CTGF, connecting tubule glomerular feedback; ZLR, Zucker lean rat; ZOR, Zucker obese rat.

Fig. 6.

Effect of benzamil treatment on P_SF in ZLR and ZOR. Inhibition of CTGF eliminates the decrease in TGF in the ZOR (○, ZLR benzamil; ●, ZOR benzamil). n = 6 in ZLR group and n = 7 in ZOR group. CTGF-Connecting tubule glomerular feedback; P_SF, stop flow pressure; ZLR, Zucker lean rat; ZOR, Zucker obese rat.

Fig. 7.

Measurement of renal damage in Zucker rats: Proteinuria was found to be elevated starting from the age of 12 wk and onwards in ZOR compared with the ZLR indicating higher renal damage in obesity. Proteinuria in ZLR and ZOR. ZOR (○) and ZLR (●). n = 8 in both ZLR group and ZOR group. *P < 0.05, ZOR vs. ZLR.